Abstract
The outcome of chemotherapy can be influenced by the host immune system at multiple levels. Chemotherapy can kill cancer cells by causing them to elicit an immune response or alternatively, by increasing their susceptibility to immune attack. In addition, chemotherapy can stimulate anticancer immune effectors either in a direct fashion or by subverting immunosuppressive mechanisms. Beyond cancer-cell-intrinsic factors that determine the cytotoxic or cytostatic response, as well as the potential immunogenicity of tumor cells, the functional state of the host immune system has a major prognostic and predictive impact on the fate of cancer patients treated with conventional or targeted chemotherapies. In this Review, we surmise that immune-relevant biomarkers may guide personalized therapeutic interventions including compensatory measures to restore or improve anticancer immune responses.
Key Points
-
It is assumed that chemotherapy acts solely on tumor cells or has immunosuppressive side effects, thus excluding that the immune system may contribute to its therapeutic success
-
Signs of immune activation, and in particular specific anticancer immune response, after chemotherapy may predict therapeutic outcome in patients
-
The composition, function, architecture and gene-expression profile of the immune infiltrate of innate and cognate immune cells in tumors has a major impact on prognosis of most major cancers
-
The presence of CD45RO+ CD8+ memory effector T cells deep in the tumor parenchyma, as well as the local production and/or action of interferon-γ, has a positive prognostic impact
-
Loss-of-function alleles of the Toll-like receptor 4 and purinergic receptor P2RX7 are negative predictors of the response to adjuvant chemotherapy with anthracyclines or oxaliplatin
-
Optimal, personalized cancer therapy will rely on the evaluation of immunological biomarkers—both from the tumor and the immune system—and on compensatory measures that correct defects in the anticancer immune response
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Disis, M. L. Immune regulation of cancer. J. Clin. Oncol. 28, 4531–4538 (2010).
Finn, O. J. Cancer immunology. N. Engl. J. Med. 358, 2704–2715 (2008).
Kantoff, P. W. et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J. Clin. Oncol. 28, 1099–1105 (2010).
Kenter, G. G. et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N. Engl. J. Med. 361, 1838–1847 (2009).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Rosenberg, S. A. & Dudley, M. E. Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr. Opin. Immunol. 21, 233–240 (2009).
Petersen, S. L. Alloreactivity as therapeutic principle in the treatment of hematologic malignancies. Studies of clinical and immunologic aspects of allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. Dan. Med. Bull. 54, 112–139 (2007).
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
Leary, R. J. et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci. Transl. Med. 2, 20ra14 (2010).
Segal, N. H. et al. Epitope landscape in breast and colorectal cancer. Cancer Res. 68, 889–892 (2008).
Van Der Bruggen, P. et al. Tumor-specific shared antigenic peptides recognized by human T cells. Immunol. Rev. 188, 51–64 (2002).
Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).
Bartek, J., Hodny, Z. & Lukas, J. Cytokine loops driving senescence. Nat. Cell Biol. 10, 887–889 (2008).
Raulet, D. H. & Guerra, N. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat. Rev. Immunol. 9, 568–580 (2009).
Smyth, M. J., Dunn, G. P. & Schreiber, R. D. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv. Immunol. 90, 1–50 (2006).
Koebel, C. M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–907 (2007).
Algarra, I., Garcia-Lora, A., Cabrera, T., Ruiz-Cabello, F. & Garrido, F. The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape. Cancer Immunol. Immunother. 53, 904–910 (2004).
Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat. Rev. Immunol. 6, 715–727 (2006).
Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008).
Reits, E. A. et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203, 1259–1271 (2006).
van der Most, R. G. et al. Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth. PLoS ONE 4, e6982 (2009).
Ramakrishnan, R. et al. Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J. Clin. Invest. 120, 1111–1124 (2010).
Boni, A. et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 70, 5213–5219 (2010).
Chiappori, A. A., Soliman, H., Janssen, W. E., Antonia, S. J. & Gabrilovich, D. I. INGN-225: a dendritic cell-based p53 vaccine (Ad.p53-DC) in small cell lung cancer: observed association between immune response and enhanced chemotherapy effect. Expert Opin. Biol. Ther. 10, 983–991 (2010).
Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005).
Obeid, M. et al. Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ. 14, 1848–1850 (2007).
Ghiringhelli, F. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 56, 641–648 (2007).
Carson, W. E. 3rd, Shapiro, C. L., Crespin, T. R., Thornton, L. M. & Andersen, B. L. Cellular immunity in breast cancer patients completing taxane treatment. Clin. Cancer Res. 10, 3401–3409 (2004).
Suzuki, E., Kapoor, V., Jassar, A. S., Kaiser, L. R. & Albelda, S. M. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer Res. 11, 6713–6721 (2005).
Vincent, J. et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 70, 3052–3061 (2010).
Borg, C. et al. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J. Clin. Invest. 114, 379–388 (2004).
Menard, C. et al. Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res. 69, 3563–3569 (2009).
Formenti, S. C. & Demaria, S. Systemic effects of local radiotherapy. Lancet Oncol. 10, 718–726 (2009).
Tsai, M. H. et al. Gene expression profiling of breast, prostate, and glioma cells following single versus fractionated doses of radiation. Cancer Res. 67, 3845–3852 (2007).
Pages, F. et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353, 2654–2666 (2005).
Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).
Pages, F. et al. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29, 1093–1102 (2010).
Martin, F., Ladoire, S., Mignot, G., Apetoh, L. & Ghiringhelli, F. Human FOXP3 and cancer. Oncogene 29, 4121–4129 (2010).
Pages, F. et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J. Clin. Oncol. 27, 5944–5951 (2009).
Mlecnik, B. et al. Biomolecular network reconstruction identifies T cell homing factors associated with survival in colorectal cancer. Gastroenterology 138, 1429–1440 (2010).
Ogino, S. et al. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin. Cancer Res. 15, 6412–6420 (2009).
Rody, A. et al. T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res. 11, R15 (2009).
Hiraoka, K. et al. Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br. J. Cancer 94, 275–280 (2006).
Dieu-Nosjean, M. C. et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J. Clin. Oncol. 26, 4410–4417 (2008).
Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).
Sato, E. et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl Acad. Sci. USA 102, 18538–18543 (2005).
Clemente, C. G. et al. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77, 1303–1310 (1996).
Gao, Q. et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J. Clin. Oncol. 25, 2586–2593 (2007).
Sharma, P. et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc. Natl Acad. Sci. USA 104, 3967–3972 (2007).
Bamias, A. et al. Correlation of NK T-like CD3+CD56+ cells and CD4+CD25+(hi) regulatory T cells with VEGF and TNFalpha in ascites from advanced ovarian cancer: Association with platinum resistance and prognosis in patients receiving first-line, platinum-based chemotherapy. Gynecol Oncol. 108, 421–427 (2008).
Hornychova, H. et al. Tumor-infiltrating lymphocytes predict response to neoadjuvant chemotherapy in patients with breast carcinoma. Cancer Invest. 26, 1024–1031 (2008).
Denkert, C. et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J. Clin. Oncol. 28, 105–113 (2010).
Ray-Coquard, I. et al. Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 69, 5383–5391 (2009).
Apetoh, L. et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol. Rev. 220, 47–59 (2007).
Zitvogel, L. et al. The anticancer immune response: indispensable for therapeutic success? J. Clin. Invest. 118, 1991–2001 (2008).
Tesniere, A. et al. Immunogenic cancer cell death: a key-lock paradigm. Curr. Opin. Immunol. 20, 504–511 (2008).
Panaretakis, T. et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J. 28, 578–590 (2009).
Tesniere, A. et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29, 482–491 (2010).
Panaretakis, T. et al. The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ. 15, 1499–1509 (2008).
Peng, R. Q. et al. Expression of calreticulin is associated with infiltration of T-cells in stage IIIB colon cancer. World J. Gastroenterol. 16, 2428–2434 (2010).
Wemeau, M. et al. Calreticulin exposure on malignant blasts predicts a cellular anticancer immune response in patients with acute myeloid leukemia. Cell Death Dis. 1, e104 (2010).
Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138, 286–299 (2009).
Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).
Martins, I. et al. Chemotherapy induces ATP release from tumor cells. Cell Cycle 8, 3723–3728 (2009).
Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).
Bianchi, M. E. HMGB1 loves company. J. Leukoc. Biol. 86, 573–576 (2009).
Sluyter, R., Shemon, A. N. & Wiley, J. S. Glu496 to Ala polymorphism in the P2X7 receptor impairs ATP-induced IL-1 beta release from human monocytes. J. Immunol. 172, 3399–3405 (2004).
Arbour, N. C. et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat. Genet. 25, 187–191 (2000).
Martins, I. et al. Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress. Oncogene doi:10.1038/onc.2010.500
Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).
Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).
Dhodapkar, K. M. et al. Natural immunity to pluripotency antigen OCT4 in humans. Proc. Natl Acad. Sci. USA 107, 8718–8723 (2010).
Battaglia, A. et al. Selective changes in the immune profile of tumor-draining lymph nodes after different neoadjuvant chemoradiation regimens for locally advanced cervical cancer. Int. J. Radiat. Oncol. Biol. Phys. 76, 1546–1553 (2010).
Zalcman, G. et al. Monitoring of p53 autoantibodies in lung cancer during therapy: relationship to response to treatment. Clin. Cancer Res. 4, 1359–1366 (1998).
Nesslinger, N. J. et al. Standard treatments induce antigen-specific immune responses in prostate cancer. Clin. Cancer Res. 13, 1493–1502 (2007).
Tsavaris, N., Kosmas, C., Vadiaka, M., Kanelopoulos, P. & Boulamatsis, D. Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes. Br. J. Cancer 87, 21–27 (2002).
Ladoire, S. et al. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin. Cancer Res. 14, 2413–2420 (2008).
de Kruijf, E. M. et al. The predictive value of HLA class I tumor cell expression and presence of intratumoral Tregs for chemotherapy in patients with early breast cancer. Clin. Cancer Res. 16, 1272–1280 (2010).
Ashida, A. et al. Expression profiling of esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy: clinical implications. Int. J. Oncol. 28, 1345–1352 (2006).
Taylor, C. et al. Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy. Clin. Cancer Res. 13, 5133–5143 (2007).
Perez, S. A. et al. CD4+CD25+ regulatory T-cell frequency in HER-2/neu (HER)-positive and HER-negative advanced-stage breast cancer patients. Clin. Cancer Res. 13, 2714–2721 (2007).
Horlock, C. et al. The effects of trastuzumab on the CD4+CD25+FoxP3+ and CD4+IL17A+ T-cell axis in patients with breast cancer. Br. J. Cancer 100, 1061–1067 (2009).
Reyal, F. et al. A comprehensive analysis of prognostic signatures reveals the high predictive capacity of the proliferation, immune response and RNA splicing modules in breast cancer. Breast Cancer Res. 10, R93 (2008).
Hsu, D. S. et al. Immune signatures predict prognosis in localized cancer. Cancer Invest. 28, 765–773 (2010).
Staaf, J. et al. Identification of subtypes in human epidermal growth factor receptor 2--positive breast cancer reveals a gene signature prognostic of outcome. J. Clin. Oncol. 28, 1813–1820 (2010).
Desmedt, C. et al. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin. Cancer Res. 14, 5158–5165 (2008).
Naito, Y. et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 58, 3491–3494 (1998).
Gianni, L. et al. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J. Clin. Oncol. 23, 7265–7277 (2005).
Acknowledgements
G. Kroemer is supported by the Ligue Nationale contre le Cancer (Equipes labelisée), Agence Nationale pour la Recherche, European Commission (Active p53, Apo-Sys, ChemoRes, ApopTrain), Fondation pour la Recherche Médicale, Institut National du Cancer and Cancéropôle Ile-de-France.
Author information
Authors and Affiliations
Contributions
L. Zitvogel, O. Kepp and G. Kroemer contributed equally to researching the data for the article, writing the article and to reviewing and/or editing of the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Zitvogel, L., Kepp, O. & Kroemer, G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8, 151–160 (2011). https://doi.org/10.1038/nrclinonc.2010.223
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrclinonc.2010.223
This article is cited by
-
Clinical verification of the relationship between serum lipid metabolism and immune activity in breast cancer patients treated with neoadjuvant chemotherapy
European Journal of Medical Research (2023)
-
A novel prognostic model based on immunogenic cell death-related genes for improved risk stratification in hepatocellular carcinoma patients
Journal of Cancer Research and Clinical Oncology (2023)
-
Differences in tumor-infiltrating lymphocyte density and prognostic factors for breast cancer by patient age
World Journal of Surgical Oncology (2022)
-
Relationship between serum lipid levels and the immune microenvironment in breast cancer patients: a retrospective study
BMC Cancer (2022)
-
Proteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies
Nature Communications (2022)