UCSF

Capitalizing on natural immune response capabilities to eradicate cancer holds great promise, but patient reach remains limited due to an incomplete understanding of how to effectively reorient immune responses to reject cancer. We are learning that effective therapeutics drive new systemic immune responses rather than relying on reinvigoration. The present body of work builds a systemic understanding of cancer immunology by defining both local and peripheral immune consequences of tumor development across a wide range of tumor models. This immune macroenvironment in cancer is universally disrupted by tumor burden, with distinct changes across cancer contexts impacted by both cancer cell type and anatomical location. Importantly, tumor disruption of the immune macroenvironment causes functional deficits in de novo adaptive immune responses to secondary immune challenges. Successful surgical tumor resection reverses the majority of changes in systemic immunity and restores functional capacity. PD-L1 checkpoint blockade or CD40 agonism immunotherapies can reorient systemic immune responses, but the preexisting immune macroenvironment influences their efficacy and immunological impact. PD-L1 blockade succeeds in cancer settings with preexisting peripheral immune engagement, while CD40 agonism is sufficient to trigger new systemic immune responses that overcome tumor immune evasion. Thus, the immune macroenvironment is a critical, yet underappreciated, differentiator in cancer that can be used to rationally select immunotherapies across patients.