Discussion

Blackwelletal2015-Helminthinfectionfecundityandageoffirstpregnancyinwomen.pdf

PARASITOLOGY

Helminth infection, fecundity, and age of first pregnancy in women Aaron D. Blackwell,1,2,3* Marilyne A. Tamayo,4 Bret Beheim,2,5

Benjamin C. Trumble,1,2,3,6,7 Jonathan Stieglitz,2,5,8 Paul L. Hooper,2,9

Melanie Martin,1,2,3 Hillard Kaplan,2,5 Michael Gurven1,2,3

Infection with intestinal helminths results in immunological changes that influence co-infections, and might influence fecundity by inducing immunological states affecting conception and pregnancy. We investigated associations between intestinal helminths and fertility in women, using 9 years of longitudinal data from 986 Bolivian forager-horticulturalists, experiencing natural fertility and 70% helminth prevalence. We found that different species of helminth are associated with contrasting effects on fecundity. Infection with roundworm (Ascaris lumbricoides) is associated with earlier first births and shortened interbirth intervals, whereas infection with hookworm is associated with delayed first pregnancy and extended interbirth intervals. Thus, helminths may have important effects on human fertility that reflect physiological and immunological consequences of infection.

D ysregulated immune function, and in par- ticular autoimmune disease, has negative impacts on virtually every aspect of fecun- dity, including ovarian function, implan- tation, and pregnancy loss (1, 2). Healthy

pregnancy is also associated with shifts in im- mune responses. During the luteal phase of the menstrual cycle, regulatory and type 2 (TH2) T cell responses increase (3). If conception occurs, these shifts continue through pregnancy (4) and help to suppress type 1 (TH1) T cell responses, increasing maternal tolerance of an immunolog- ically distinct fetus (3). Because pregnancy is both affected by and alters immunity, parasites that result in systemic immunological changes might be expected to affect fecundity by alter- ing the host’s immune responses. Helminths, such as hookworm (Ancylostoma duodenale or Necator americanus) and giant roundworm (Ascaris lumbricoides), each infect 500 million to 800 million people (5) and are associated with immunological changes, such that host helper T cell populations generally shift from TH1 to- ward TH2 responses (6, 7) and the suppressive activity of regulatory T cells increases to mod- ulate both TH1 and TH2 responses (8, 9). These shifts can alter susceptibility to other infectious diseases, such as malaria (10), giardiasis (11), and tuberculosis (12); are associated with reductions in many diseases that have inflammatory or auto-

immune etiology (13); and also resemble the T cell patterns that occur during pregnancy. In humans, some helminth parasites can di-

rectly infect the reproductive organs or the fetus; for example, the filarial roundworm,Wuchereria bancrofti, can cause elephantiasis of the genitals (14). Animal studies have also examined life his- tory changes associated with parasitism (15). Yet there are few data on the effects of intestinal helminth infections on human fecundity, fer- tility, or birth spacing. We prospectively exam- ined the effect of helminth infection on the fecundity of women. We used 9 years of longi- tudinal data collected on 986 Tsimane forager- horticulturalist women living in the Amazonian lowlands of Bolivia (table S1). Tsimane are pre- dominantly a natural fertility population, with infrequent (<5% prevalence) use of pharmaceu- tical contraceptives and a total fertility rate of nine births per woman (16). Helminths infect

70% of the population, the most common being hookworm (56%) and A. lumbricoides (15 to 20%) (11, 17). In both animal and human studies, parasites

have been shown to influence host reproduction via sexual behavior, brood or litter size, offspring size, incubation periods, conception rates, and pregnancy loss (18–22). Inmost cases, parasitism reduces host reproduction by compromising reproductive organs or reducing energy budgets (14, 23). However, among Tsimane adults, mor- bidity from intestinal helminth infections is low, particularly for A. lumbricoides. Controlling for age and co-infection in our sample, hookworm infection is associated with slightly lower body mass index (BMI) (generalized linear model, b = –0.77 kg/m2, P < 0.001) and hemoglobin (b = –0.19 g/dl, P = 0.005), whereas A. lumbricoides is not (b = –0.34 kg/m2, P = 0.180; b = –0.07 g/dl, P = 0.413). However, helminth infection is also associatedwith reductions in other infections, such as the intestinal protist Giardia lamblia (11). We hypothesized that intestinal helminths might in- crease fecundity because the associated immuno- logical changes, resembling those occurring during pregnancy, modulate inflammatory responses that might otherwise impair fertility. By using Cox proportional hazards models, we

tested whether helminth infection was associ- ated with changes in birth spacing for 561 multi- parous women and the age of first pregnancy (AFP) for 425 nulliparous women (24). Con- sistent with our hypothesis, compared to being uninfected, A. lumbricoides infection was asso- ciated with an earlier AFP hazard ratio [(HR) = 3.06, confidence interval (CI) 1.91 to 4.91,P<0.001 (Fig. 1 and Table 1)] and an increased hazard of pregnancy under age 32 years (at age 20:HR= 1.64, CI 1.16 to 2.33, P = 0.005). This association declines with age (interaction between A. lum- bricoides and age: HR = 0.68 per decade, CI 0.51 to 0.89, P = 0.006) and becomes significantly negative by the age of 46 years (HR = 0.62, CI 0.38 to 1.00, P = 0.05). However, these late-life

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1Department of Anthropology, University of California Santa Barbara, CA 93106, USA. 2Tsimane Health and Life History Project, San Borja, Bolivia. 3Broom Center for Demography, University of California Santa Barbara, CA 93106, USA. 4Department of Anthropology, University of Missouri, Columbia, MO 65211, USA. 5Department of Anthropology, University of New Mexico, Albuquerque, NM 87131, USA. 6Center for Evolutionary Medicine, Arizona State University, Tempe, AZ 85287, USA. 7School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, USA. 8Institute for Advanced Study in Toulouse, Toulouse, France. 9Department of Anthropology, Emory University, Atlanta, GA 30322, USA. *Corresponding author. E-mail: [email protected]

Fig. 1. Associations between infection and likelihood of becoming pregnant. (A to C) Kaplan-Meier curves from Cox proportional hazard models (table S2), representing the time to first pregnancy (A), and time to subsequent pregnancies at age 25 years (B) and age 40 years (C). Hazard ratios for conception associated with infection across ages are shown in (D). Colors indicate uninfected (dashed brown), infected with hookworm (solid dark green), or infected with A. lumbricoides (solid yellow).

RESEARCH | REPORTS

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negative associations are outweighed by pos- itive associations during early life, such that a woman with A. lumbricoides, projected across her life span, would expect to have two more children than a woman who was never infected (Fig. 2). In contrast, infection with hookworm was as-

sociated with a delayed age of first pregnancy (HR = 0.33, CI 0.20 to 0.54, P < 0.001) and a reduced hazard of subsequent pregnancies at all

ages (HR = 0.71, CI 0.58 to 0.86, P < 0.001). A woman chronically infected with hookworm would be predicted to have three fewer children than an uninfectedwoman (Fig. 2). We found no interaction between infections, such that co- infection is associated with the additive effects of hookworm and A. lumbricoides. These results are not altered by controlling

for other likely confounds affecting fecundity or fecundity-altering behaviors, including phys-

ical condition, education (a proxy of accultura- tion), village location, season, and secular changes, even though these variables do affect fertility [tables S2 and S3, also see (25)]. The results are also not mediated by other comorbid infections or illnesses (table S4). Twenty percent of infected women were given antihelminthic drugs during medical visits. Receipt of antihelminthics was itself associated with a lower hazard of conceiv- ing (HR = 0.75, CI 0.58 to 0.97, P = 0.03); how- ever, neither controlling for treatment in models nor excluding these women appreciably altered hazard ratios from infection with either hook- worm or A. lumbricoides. The results are also not driven by changing infection hazard during pregnancy. Although pregnancy is associated with an increased likelihood of hookworm infec- tion, particularly in late pregnancy (table S6 and fig. S8), this relationship does not mediate the association between infection and conception hazards (24). Instead, it appears that hookworm- infectedwomen occasionally clear their infections, during which time they become pregnant, fol- lowed quickly by subsequent reinfection with hookworm. Lastly, these associations are unlike- ly to be caused by consistent differences between individual women (e.g., genetic pleiotropies) that affect both fertility and risk of infection, because past parity is unrelated to likelihood of current infection [hookworm: odds ratio (OR) = 0.98 per birth, CI 0.90 to 1.08, P = 0.65; A. lumbricoides: OR 1.05 per birth, CI 0.93 to 1.18, P = 0.46]. Finding that hookworm and A. lumbricoides

have contrasting associations with fecundity may seem unexpected. However, we suggest two reasons why we might observe such a pattern. First, although helminths are often discussed as if interchangeable, hookworm and A. lum- bricoides do not have identical effects on the immune system. Whereas A. lumbricoides is

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Table 1. Cox proportional hazard models. Models also include generalized estimating equation cluster terms for individual and village. For each model, the

number of individuals (n), number of medical observations (obs), and number of observed pregnancies (preg) are given. Dashes indicate variables not

applicable for a given model or excluded by AIC. Details and additional excluded variables are given in tables S2 and S3.

Age of first pregnancy

(n = 425, obs = 639, preg = 87)

Time to next pregnancy

(n = 561, obs = 1623, preg = 405)

Variable Exp(b) 95% CI P Exp(b) 95% CI P

Age (decades)* – – – 1.00 (0.80–1.25) 0.992 .. .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .

Age4 (decades)* – – – 0.95 (0.93–0.96) <0.001 .. .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .

Hookworm 0.34 (0.20–0.58) <0.001 0.74 (0.60–0.91) 0.004 .. .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .

A. lumbricoides† 3.06 (1.91–4.91) <0.001 1.64 (1.16–2.33) 0.005 .. .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .

A. lumbricoides × age* – – – 0.68 (0.51–0.89) 0.006 .. .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .

Treatment with antihelminthic 0.43 (0.19-0.97) 0.042 0.75 (0.58–0.97) 0.027 .. .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .

Education (years) – – – 0.92 (0.86–0.99) 0.017 .. .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .

Speaks Spanish – – – 0.74 (0.57–0.95) 0.018 .. .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .

Distance to town (10 km) – – – 0.96 (0.91–1.00) 0.075 .. .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .

Season (P-spline) – – <0.001 – – <0.001 .. .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .. ... ... .. ... .. ... ... .. ... ... .

*Age is centered at 20 years. Age was continuous to the nearest tenth of a year but is shown in decades to make the parameters more easily interpretable. Because age- related changes in fecundity are nonlinear, transformations ranging from age2 to age5 were compared by AIC to select the age transformation (age4) that best fit the data (fig. S3). †For the time to next pregnancy model, the roundworm parameter represents the hazard ratio at age 20.

Fig. 2. Reproductive careers predicted from Cox proportional hazard models, show- ing the expected dis- tributions of reproductive values for hypothetical women with persis- tent parasite status throughout life.Out- comes include age at first birth (A), interbirth intervals (B), age at last birth (C), age-specific fertility (births/woman per year) (D), median cumulative fertility over time (E), and total completed fertility by age 50 (F). Colors indicate uninfected (U, brown), infected with hookworm (H, dark green), infected with A. lumbricoides (A, yellow), or co-infected with hookworm and A. lumbricoides (C, light blue). Box plot whiskers display the 5th and 95th percentiles; bodies, the 25th, 50th, and 75th. Predictions are derived from the models in Fig. 1.

RESEARCH | REPORTS

associated with a polarized TH2 response (6), the response to hookworm has been reported as a mixed TH1/TH2 response (26, 27). Hookworm and A. lumbricoides also have differing effects on other diseases, such asmalaria (10). Thus, the response to A. lumbricoides may be more favor- able to conception and implantation, because it more closely resembles the immunological state in pregnancy and less closely resembles pro- inflammatory states that suppress fecundity. Second, hookworm infection may be more cost- ly than A. lumbricoides infection, such that the costs imposed by infection, such as anemia and nutritional loss, outweigh any effect of immune modulation. Althoughwe do not have direct mea- sures of parasite load, hookworm is associated with both lower BMI and lower hemoglobin for women in our sample, whereas A. lumbricoides is not. Future studies will need to investigate the importance of parasite burden in these associations. Although consistent with our hypothesis, it

is still unexpected to see positive associations between fecundity and A. lumbricoides infection, given that most parasites decrease reproduction. However, this associationmight instead be under- stood not as de novo increases in fecundity, but as the suppression of responses that would other- wise decrease fecundity. For example, most orga- nisms down-regulate reproductive effort during acute illness because inflammation suppresses reproductive function (28). If A. lumbricoides infection modulates inflammatory responses, then it might also limit inflammation-induced reproductive suppression, as well as sickness be- havior and associated reductions in sexual activity (29, 30). If so, then the effects of A. lumbricoides might only be observed in the presence of other illnesses or conditions resulting in excess inflam- mation. An additional possibility is that the increase in fertility represents fecundity compensation, a host response in which reproductive effort is shifted toward earlier ages to compensate for increasing morbidity or mortality (15). However, our analysis cannot fully evaluate these kinds of lifetime or cumulative effects, because our lon- gitudinal sample remains short relative to the human life span. Regardless of mechanism, these results indi-

cate that across populations, helminths may have unappreciated effects on demographic patterns, particularly given their high global prevalences (5).

REFERENCES AND NOTES

1. H. J. A. Carp, C. Selmi, Y. Shoenfeld, J. Autoimmun. 38, J266–J274 (2012).

2. A. Sen, V. A. Kushnir, D. H. Barad, N. Gleicher, Nat. Rev. Endocrinol. 10, 37–50 (2014).

3. T. T. Jiang et al., J. Immunol. 192, 4949–4956 (2014). 4. A. L. Veenstra van Nieuwenhoven, M. J. Heineman, M. M. Faas,

Hum. Reprod. Update 9, 347–357 (2003). 5. P. J. Hotez et al., J. Clin. Invest. 118, 1311–1321 (2008). 6. S. M. Geiger et al., Parasite Immunol. 24, 499–509 (2002). 7. R. M. Maizels, M. Yazdanbakhsh, Nat. Rev. Immunol. 3,

733–744 (2003). 8. L. J. Wammes et al., Eur. J. Immunol. 40, 437–442 (2010). 9. E. van Riet, F. C. Hartgers, M. Yazdanbakhsh, Immunobiology

212, 475–490 (2007). 10. J. A. Fernández-Niño et al., Trans. R. Soc. Trop. Med. Hyg. 106,

701–708 (2012).

11. A. D. Blackwell, M. Martin, H. Kaplan, M. Gurven, Proc. Biol. Sci. 280, 20131671 (2013).

12. V. O. Ezenwa, A. E. Jolles, Science 347, 175–177 (2015). 13. L. J. Wammes, H. Mpairwe, A. M. Elliott, M. Yazdanbakhsh,

Lancet Infect. Dis. 14, 1150–1162 (2014). 14. J. McFalls, A. Joseph, M. H. McFalls, Disease and Fertility

(Academic Press, Orlando, FL, 1984). 15. M. Forbes, Oikos 67, 444–450 (1993). 16. L. McAllister, M. Gurven, H. Kaplan, J. Stieglitz, Am. J. Hum.

Biol. 24, 786–799 (2012). 17. M. Martin, A. D. Blackwell, M. Gurven, H. Kaplan, in Primates,

Pathogens, and Evolution, J. Brinkworth, K. Pechenkina, Eds. (Springer, New York, 2013), pp. 363–387.

18. A. Møller, J. Anim. Ecol. 62, 309–322 (1993). 19. H. Hurd, Trends Parasitol. 17, 363–368 (2001). 20. P. Neuhaus, Proc. Biol. Sci. 270 (suppl. 2), S213–S215 (2003). 21. L. Krishnan, L. J. Guilbert, T. G. Wegmann, M. Belosevic,

T. R. Mosmann, J. Immunol. 156, 653–662 (1996). 22. R. Avitsur, R. Yirmiya, Pharmacol. Biochem. Behav. 64,

787–796 (1999). 23. M. Baudoin, Evolution 29, 335–352 (1975). 24. Materials and methods are available as supplementary

materials on Science Online. 25. H. Kaplan, P. L. Hooper, J. Stieglitz, M. Gurven, in Population in

the Human Sciences: Concepts, Models, Evidence, Philip Kreager, B. Winne, S. Ulijaszek, C. Capelli, Eds. (Oxford Univ. Press, Oxford, 2015), pp. 361–378.

26. S. M. Geiger et al., PLOS Negl. Trop. Dis. 5, e1280 (2011). 27. H. J. McSorley, A. Loukas, Parasite Immunol. 32, 549–559 (2010). 28. K. B. H. Clancy et al., Am. J. Hum. Biol. 25, 389–398 (2013).

29. J. Stieglitz et al., Brain Behav. Immun. 49, 130–139 (2015). 30. E. C. Shattuck, M. P. Muehlenbein, Am. J. Phys. Anthropol. 157,

1–18 (2015).

ACKNOWLEDGMENTS

We thank the Tsimane for their continued participation; our Bolivian project staff, including D. Eid, I. Maldonado, E. Cortez, N. Zabala, and many others; and four anonymous reviewers for their helpful comments. This work was supported by grants from the NIH/National Institute on Aging (R01AG024119, R56AG024119, P01AG022500) and the NSF (BCS-0422690). Data described in this paper are available as supplementary online materials. The study was reviewed and approved by the Gran Consejo Tsimane, the governing body overseeing Tsimane affairs, and by the institutional review boards of the University of California, Santa Barbara, and the University of New Mexico.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/350/6263/970/suppl/DC1 Materials and Methods Supplementary Text Figs. S1 to S8 Tables S1 to S7 References (31–44) Databases S1 and S2

12 June 2015; accepted 9 October 2015 10.1126/science.aac7902

CANCER IMMUNOLOGY

Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1 Erika Vacchelli,1,2,3,4,5* Yuting Ma,1,2,3,4,5,6,7* Elisa E. Baracco,1,2,3,8 Antonella Sistigu,9

David P. Enot,1,2,3,10 Federico Pietrocola,1,2,3,8 Heng Yang,1,2,3,4,5,6,7 Sandy Adjemian,1,2,3

Kariman Chaba,1,2,3,4 Michaela Semeraro,1,11,12 Michele Signore,13 Adele De Ninno,14

Valeria Lucarini,13 Francesca Peschiaroli,13 Luca Businaro,14 Annamaria Gerardino,14

Gwenola Manic,9 Thomas Ulas,15 Patrick Günther,15 Joachim L. Schultze,15

Oliver Kepp,1,2,3,4,5 Gautier Stoll,1,2,3,4,5 Céline Lefebvre,1,16 Claire Mulot,17,18

Francesca Castoldi,1,2,3,8,19 Sylvie Rusakiewicz,1,11,12 Sylvain Ladoire,20,21,22

Lionel Apetoh,20,21,22 José Manuel Bravo-San Pedro,1,2,3,4,5 Monica Lucattelli,23

Cécile Delarasse,24 Valérie Boige,18,25 Michel Ducreux,8,25 Suzette Delaloge,16,26

Christophe Borg,27 Fabrice André,1,16,28,29 Giovanna Schiavoni,13 Ilio Vitale,9,30

Pierre Laurent-Puig,17,18,31 Fabrizio Mattei,13† Laurence Zitvogel,1,8,11,12†‡ Guido Kroemer1,2,3,4,5,10,31,32†‡

Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer.We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1−/− mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses.

T he success of anticancer chemotherapy is linked to a durable tumor-targeting immune response (1). Accordingly, the presence of tumor-infiltrating dendritic cells (DCs) and CD8+ T lymphocytes at diagnosis increases

the likelihood of breast cancer patients respond- ing to anthracyclines (2–6). One mechanism through which anthracyclines can stimulate an antitumor immunity is by inducing immuno- genic cell death (ICD), and this mechanism implies

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DOI: 10.1126/science.aac7902 , 970 (2015);350 Science

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