Endogenous tumor-reactive CD8⁺T cells are differentiated effector cells expressing high levels of CD11a and PD-1 but are unable to control tumor growth

Abstract

Immunotherapies aimed at enhancing natural or endogenous antitumor T-cell immunity in patients affected by advanced malignancies are currently being implemented in the clinic with promising results. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, reliable biomarkers are needed. We used CD11a, an integrin that is upregulated on the surface of effector and memory CD8+ T cells, and PD-1, an immunoregulatory receptor expressed by activated T cells, as biomarkers to identify, quantify and monitor endogenous tumor-reactive cytotoxic T lymphocytes (CTLs) in two mouse tumor models and in the peripheral blood of 12 patients affected by Stage IV melanoma. High expression levels of CD11a and PD-1 were detected among CD8+ T cells residing within primary and metastatic murine tumor sites, as well as in spontaneous murine breast cancer tissues. In the peripheral blood of melanoma patients, tumor antigen-specific CD8+ T cells were associated with a population of CD11ahigh CD8+ T cells that co-expressed high levels of PD-1. Healthy donors exhibited a comparatively much lower frequency of such PD-1+CD11ahighCD8+ T cells. Phenotypic analyses demonstrated that CD11ahighCD8+ T cells are proliferating (Ki67+) and activated (CD62L-CD69+). Increased CD11ahighCD8+ T cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector functions of CD8+ T cells is compromised by an elevated expression of PD-1. The CD11ahighCD8+ T-cell population expresses high levels of PD-1 and presumably constitutes the cellular target of PD-1 blockade therapy. The expression level of CD11a and PD-1 by CD8+ T cells may therefore represent a novel biomarker to identify and monitor endogenous tumor-reactive CTLs. This may not only provide an immunological readout for evaluating the efficacy of immunotherapy but also contribute to the selection of cancer patients who are likely to benefit from anti-PD-1 therapy.

PD-1 Restrains Radiotherapy-Induced Abscopal Effect

“…The observation of PD-1 blockade augmenting SABR-induced antitumor immunity is consistent with PD-1 functioning as an immune checkpoint inhibitory molecule. Since CD11a expression is required in the rejection of tumors (11), we previously established that CD11a high CD8 + T cells are a tumor-reactive population (8). Since both melanoma and RENCA tumor lines used in our experiments express B7-H1 (PD-L1; a ligand for PD-1) (12), the expression of PD-1 by CD11a high CD8 + T cells from primary and secondary tumors was examined (Figure 4).…”

“…Accordingly, PD-1 inhibition (in KO and blocking antibody models) significantly enhances SABR-induced antitumor immunity and results in the suppression of both irradiated and non-irradiated (primary and secondary, respectively) tumor growth. We have established that PD-1 expression is up-regulated in a tumor-reactive CD11a high CD8 + T-cell population and contributes to restraining the T-cell effector activity(8). Here, we confirm the correlation between the tumor-reactive CD11a high CD8 + T cells and the SABR-induced antitumor response.…”

T cell Bim levels reflect responses to anti–PD-1 cancer therapy

“…To further investigate whether PD-1 is directly involved in Bim upregulation in tumor-reactive CD8 + T cells, we isolated tumor-infiltrating lymphocytes (TILs) and measured the expression of Bim in PD-1 + tumor-reactive CD8 + T cells identified by their high expression of CD11a (20). Both PD-1 and CD11a have been established by us and others as an identifier of tumor-reactive CD8 + T cells in mouse and human melanoma systems (20, 21). As shown in Figure 1A, CD11a hi tumor-reactive CD8 + T cells, isolated from B16 mouse melanoma tumors, were divided into PD-1 + and PD-1 − subsets.…”

“…To examine whether Bim upregulation is a consequence of PD-1 and PD-L1 interaction in patients with cancer, we compared Bim levels (mean fluorescence intensity [MFI]) in tumor-reactive peripheral blood CD8 + T cells from patients with MM (newly diagnosed) to antigen-experienced CD8 + T cells from healthy donors based on their high expression of CD11a (20, 22). Tumor-reactive CD8 + T cells were identified by their expression of PD-1 (23) and CD11a in the peripheral blood of melanoma patients (20).…”

Combinatorial immunotherapy with checkpoint blockers solves the problem of metastatic melanoma—An exclamation sign with a question mark

“…It will be crucial to identify biomarkers that predict therapeutic efficacy and/or toxicity, for improving patient stratification. [23][24][25][26] Moreover, it will be essential to develop strategies for the control of inflammatory/autoimmune side effects other than treatment discontinuation and the administration of glucocorticoids. Finally, it will be important to identify novel immuno(chemo)therapeutic regimens for the management of melanoma patients who do not benefit from dual CTLA4/PD-1 blockade.…”