Decoding Cancer Immune Escape: From Microenvironmental Mechanisms to Novel Immunotherapies

Abstract

Effective anti-tumor immunity requires not only the presence of immune cells within tumors, but also their ability to recognize and eliminate cancer cells in a sustained manner. Tumors evade immune control by shaping an immunosuppressive microenvironment and driving T-cell dysfunction. Understanding the mechanisms that support effective anti-tumor responses is therefore essential for developing durable immunotherapies. In the first part of this talk, we investigate the immune landscape of breast cancer brain metastases. We identify T-cell-infiltrated immune ecotypes, tertiary lymphoid structures (TLS), and TLS-associated gene signatures linked to improved survival. Within tumor islands, we identify clonally expanded, tissue-resident memory-like CD8⁺ T cells that retain cytotoxic activity despite expressing exhaustion-associated markers. These cells recognize and kill autologous tumor cells and respond to immune checkpoint blockade, highlighting their therapeutic potential. In the second part, we explore strategies to sustain T-cell function using chronic lymphocytic leukemia (CLL) as a model. We show that IL-10 receptor signaling in CD8⁺ T cells supports their function during disease progression. Therapeutic IL-10-Fc limits CLL development in a CLL mouse model by reducing T-cell exhaustion and suppressive monocyte accumulation, and improving immune control. Combined with T-cell-engaging bispecific antibodies, IL-10-Fc enhances anti-tumor efficacy in B-cell lymphoma patient-derived 3D cultures and mouse models of CLL, while promoting immune memory. Together, these findings demonstrate that durable tumor control requires both tumor-reactive T cells and the maintenance of their functional capacity. Identifying effective T-cell populations and developing strategies to sustain their activity may help overcome immune escape and advance more durable cancer immunotherapies.