Clinical responses to anti-tumor monoclonal antibody (mAb) treatment have been regarded for many years only as a consequence of the ability of mAbs to destroy tumor cells by innate immune effector mechanisms. More recently, it has also been shown that anti-tumor antibodies can induce a long-lasting anti-tumor adaptive immunity, likely responsible for durable clinical responses, a phenomenon that has been termed the vaccinal effect of antibodies. However, some of these anti-tumor antibodies are directed against molecules expressed both by tumor cells and normal immune cells, in particular lymphocytes, and, hence, can also strongly affect the host adaptive immunity. In addition to a delayed recovery of target cells, lymphocyte depleting-mAb treatments can have dramatic consequences on the adaptive immune cell network, its rebound, and its functional capacities. Thus, in this review, we will not only discuss the mAb-induced vaccinal effect that has emerged from experimental preclinical studies and clinical trials but also the multifaceted impact of lymphocytes-depleting therapeutic antibodies on the host adaptive immunity. We will also discuss some of the molecular and cellular mechanisms of action whereby therapeutic mAbs induce a long-term protective anti-tumor effect and the relationship between the mAb-induced vaccinal effect and the immune response against self-antigens.
Preclinical models and clinical studies have shown that anti-CD20-based treatment has multifaceted consequences on T-cell immunity. We have performed a prospective study of peripheral T-cell compartment in FL patients, all exhibiting high tumor burden and receiving rituximab-chemotherapy-based regimen (R-CHOP). Before treatment, FL patients harbor low amounts of peripheral naive T cells, but high levels of CD4+ TEM, CD4+ Treg and CD8+ TEMRA subsets and significant amounts of CD38+ HLA-DR+ activated T cells. A portion of these activated/differentiated T cells also expressed PD-1 and/or TIGIT immune checkpoints. Hierarchical clustering of phenotyping data revealed that 5/8 patients with only a partial response to R-CHOP induction therapy or with disease progression segregate into a group exhibiting a highly activated/differentiated T cell profile and a markedly low proportion of naive T cells before treatment. Rituximab-based therapy induced a shift of CD4+ and CD8+ T cells toward a central memory phenotype and of CD8+ T cells to a naive phenotype. In parallel, a decrease in the number of peripheral T cells expressing both PD-1 and TIGIT was detected. These observations suggest that the standard rituximab-based therapy partially reverts the profound alterations observed in T-cell subsets in FL patients, and that blood T-cell phenotyping could provide a better understanding of the mechanisms of rituximab-based treatment.
Preclinical and clinical studies have suggested that cancer treatment with antitumor antibodies induces a specific adaptive T cell response. A central role in this process has been attributed to CD4+ T cells, but the relevant T cell epitopes, mostly derived from non-mutated self-antigens, are largely unknown. In this study, we have characterized human CD20-derived epitopes restricted by HLA-DR1, HLA-DR3, HLA-DR4, and HLA-DR7, and investigated whether T cell responses directed against CD20-derived peptides can be elicited in human HLA-DR-transgenic mice and human samples. Based on in vitro binding assays to recombinant human MHC II molecules and on in vivo immunization assays in H-2 KO/HLA-A2+-DR1+ transgenic mice, we have identified 21 MHC II-restricted long peptides derived from intracellular, membrane, or extracellular domains of the human non-mutated CD20 protein that trigger in vitro IFN-γ production by PBMCs and splenocytes from healthy individuals and by PBMCs from follicular lymphoma patients. These CD20-derived MHC II-restricted peptides could serve as a therapeutic tool for improving and/or monitoring anti-CD20 T cell activity in patients treated with rituximab or other anti-CD20 antibodies.Electronic supplementary materialThe online version of this article (10.1007/s00262-019-02389-7) contains supplementary material, which is available to authorized users.
For many years, the clinical responses observed in cancer patients treated with antitumor antibodies have been viewed only as a consequence of the recruitment and activation of innate immune cells. Several preclinical studies have indicated that anti-tumor antibodies can also induce a potent anti-tumor adaptive T-cell response capable of protecting animals from tumor challenge. Our studies have shown that CD4+ Th1 cells play a central role in the response to anti-CD20 tumor therapy by opposing Treg expansion and that CD20-specific memory T cells are responsible for anti-tumor protection observed in surviving animals subjected to tumor rechallenge. Whether an adaptive T-cell response is elicited in patients with Follicular Lymphoma (FL) receiving anti-CD20-based treatment is not known. In the present work, we analyzed peripheral T cells before and during anti-CD20-chemotherapy treatment of FL patients (R-CHOP) with high tumor burden. We first examined in ELISPOT assays the IFN-γ production by PBMC from 20 patients against human CD20-derived peptides previously selected by combining in silico and in vivo screening using transgenic human HLA-DR mice. Both FL patients before treatment and patients undergoing R-CHOP treatment exhibited peripheral T-cell responses to the selected CD20-derived peptides. However, these responses were markedly lower than those observed in healthy donors. Similar results were also obtained when T cell responses against viruses commonly infecting large numbers of individuals (CMV, EBV, influenza) were assessed, suggesting that high tumor burden FL patients exhibit an immune exhaustion of T cells. Multiparametric flow cytometry analyses suggested that their poor ability to respond to viral and CD20-derived peptides is related to the presence of an immunocompromised and exhausted blood T-cell peripheral compartment with higher percentages of TIGIT- and PD-1-expressing T cells, of peripheral Treg, and terminally differentiated CD8+ TEMRA. R-CHOP therapy induced a shift of CD4+ and CD8+ T cells toward a central memory phenotype (TCM), an additional shift of CD8+ T cells to a naive phenotype, and a decrease in the number of PD-1+ and TIGIT+ T cells, making these cells evolving toward a lesser degree of exhaustion. However, it did not restore a level of specific responses similar to those observed in healthy donors. These results support the use of anti-PD-1 and anti-TIGIT antibodies in combination with anti-CD20 in FL patients with high-tumor burden. Citation Format: Benoit Milcent, Pauline Brice, Catherine Thieblemont, Jean-Luc Teillaud, Sophie Siberil. Rituximab chemotherapy induces a partial recovery from T-cell exhaustion in follicular lymphoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5616.
We have previously shown that anti-tumor T cell response is triggered by anti-CD20-mAb in mice bearing EL4-huCD20 tumor cells, a murine tumor expressing human CD20+ (huCD20) molecule. To define huCD20-derived epitopes that might be targeted by mAb-induced adaptive responses, we have selected different candidate peptides restricted to Kb, Db, and I-Ab, based on in silico prediction and in vitro binding to recombinant MHC molecules. Naive C57Bl/6 mice were then immunized with different mixtures of these peptides and subsequently challenged with EL4-huCD20 tumor cells. A longer survival could be achieved in mice immunized with MHCI and MHCII huCD20-derived peptide mixtures corresponding to various regions of the human CD20 molecule. Then, we defined in the same regions twenty-three huCD20-derived peptides with high in vitro binding to human MHCI and MHCII molecules frequent in Caucasian populations. The use of humanized HLA-DR1/HLA-A2.1 transgenic mice injected with EL4-huCD20 tumor cells and of NIH/3T3 cells expressing accessory and human HLA-DR1 or A2.1 molecules loaded with the candidate peptides made it possible to define 4 MHCI-restricted and 13 MHCII-restricted CD20-derived peptides capable of stimulating IFN-gamma production by specific CD4+ and CD8+ T cells. These findings support further studies on the identification and characterization of CD20-specific T cells in anti-CD20-treated follicular lymphoma patients. The definition of CD20-derived immunogenic epitopes also paves the way for the search of new biomarkers correlating with the clinical outcome of patients. Citation Format: Sophie Siberil, Benoit Milcent, Quentin Riller, Claire Deligne, Mohamad Hamieh, Olivier Toutirais, Jean-Baptiste Latouche, Jean-Luc Teillaud. Deciphering CD20 immunogenicity to generate protective anti-tumor CD4+ and CD8+ T cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B119.
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