Immune evasion in primary central nervous system lymphoma: macrophage and T cell roles in response to immunotherapy

Abstract

Primary central nervous system lymphoma is an aggressive extranodal lymphoma with poor prognosis, largely due to its capacity for immune evasion within the unique microenvironment of the CNS. Here, we investigated the interactions between macrophages and T cells in a syngeneic mouse model of PCNSL, manipulating macrophage/microglia populations and MHC class I expression on tumor cells to mimic patient-associated immune escape. We found that macrophages and microglia are indispensable for anti-tumor immunity and significantly enhance the efficacy of PD1 checkpoint blockade, particularly when tumor cells retain MHCI expression. In contrast, depletion of these myeloid cells led to accelerated disease progression and diminished response to immunotherapy, highlighting the importance of both innate and adaptive immunity in PCNSL. Interestingly, MHC-I–deficient PCNSL did not respond to T cell–based therapies and was controlled exclusively by macrophages, rendering prognosis largely dependent on this alteration. Our findings support the need for therapeutic strategies that target both T cell and myeloid compartments and suggest that profiling MHC-I expression may help guide personalized immunotherapy approaches in this challenging disease.