A novel method to identify and monitor endogenous tumor-reactive T cells by high expression of CD11a (LFA-1) and PD-1 (CD279) as immunologic readout for evaluating the efficacy of PD-1 blockade.

Abstract

3037 Background: Tumor immunotherapies directed towards enhancing natural or endogenous anti-tumor T-cell immunity in patients with advanced malignancies are currently being implemented in clinic with promising results. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, a reliable T-cell marker is needed. Methods: We utilized CD11a (LFA-1, lymphocyte functional-associated antigen 1), an integrin up-regulated on effector and memory CD8 T-cells, and PD-1 (programmed death-1), an immunoregulatory receptor expressed by activated T cells, as biomarkers to identify, quantitate and monitor endogenous tumor-reactive cytotoxic lymphocytes (CTLs) in two mouse tumor models and the peripheral blood (PB) of 12 patients with stage IV melanoma. Results: High expression of CD11a and PD-1 was identified among CD8 T-cells residing within primary and metastatic murine tumor sites, as well as in spontaneous murine breast cancer tissues. In the PB of melanoma patients, tumor antigen-specific CD8 T cells were associated with a population of CD11a high CD8 T-cells which co-expressed high levels of PD-1, as opposed to eleven healthy donors who had a much lower frequency of PD-1+ CD11a high CD8 T-cells (p <0.0001). Phenotypic analysis showed that CD11a high CD8 T-cells are proliferating (Ki67 positive) activated (CD62L low, CD69 high) T-cells. Increased CD11a high CD8 T-cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector function of CD8 T cells is compromised by co-expression of elevated levels of PD-1. Conclusions: CD11a high CD8 T-cell population expresses high levels of PD-1 and is likely the cellular target of PD-1 blockade therapy. High expression of CD11a (LFA-1) and PD-1 (CD279) by CD8 T-cells may 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 therapy, but also contribute to the selection of patients with solid malignancies likely to benefit from anti-PD-1 therapy.