Association between Intratumoral CD8+ T Cells with FoxP3+ and CD163+ Cells: A Potential Immune Intrinsic Negative Feedback Mechanism for Acquired Immune Resistance

SIMPLE SUMMARY: The cancer immunoediting theory states that tumor evolution is based on continuous and dynamic interactions between the immune system and tumor cells. Through these interactions, the endogenous antitumor immunity (EAI) is generated, which exerts a selective pressure to sculpt tumor phenotypes throughout all stages of tumor development. However, following chronic stimulation by tumor cells, immune lymphocytes express an “exhausted” phenotype and become anergic. Thus, therapies that reactivate the EAI (primarily immunotherapies) are most effective for inducing long-lasting clinical results. Nevertheless, the majority of patients relapse after an initial response to immunotherapies. The reason for this is that tumors develop acquired immune resistance (AIR) suppressing the EAI. In this study, we demonstrate that high frequencies of CD163+ and FoxP3+ cells in the tumors of patients with breast cancer co-exist with CD8+ cells only when the latter are also in dense frequencies. This type of AIR is associated with poor overall survival. ABSTRACT: Acquired immune resistance (AIR) describes a situation in which cancer patients who initially responded clinically to immunotherapies, after a certain period of time, progress with their disease. Considering that AIR represents a feedback response of the tumor against the immune attack generated during the course of immunotherapies, it is conceivable that AIR may also occur before treatment initiation as a mechanism to escape endogenous adaptive antitumor immunity (EAAI). In the present study, we assessed the EAAI in paraffin-embedded breast primary tumor tissue samples and drew correlations with the clinical outcomes. In particular, we analyzed densities of CD8+ cells as elements mediating antitumor cytotoxicity, and of CD163+ and FoxP3+ cells as suppressor elements. We found a direct correlation between the densities of CD8+ cells and of CD163+ and/or FoxP3+ cells in the vast majority of patients’ tumors. Importantly, the vast majority of patients whose tumors were overpopulated by CD8+ cells developed AIR, which was characterized by high intratumoral CD163+ and/or FoxP3+ cell densities and reduced overall survival (OS). We also showed that AIR depends on the levels of CD8+ cell-ratios in the tumor center to the invasive margin. Our data suggest that tumors develop AIR only when under a robust endogenous immune pressure.