Inflamed and noninflamed lymphoma environments. (A) A noninflamed lymphoma environment. This lymphoma lacks infiltration by T cells. Oncogenic alterations that may contribute to poor immune cell infiltration/activation in noninflamed lymphomas are shown (PTEN, EZH2, TP53, MYC). Because of the lack of immune recognition, genetic alterations associated with escape from immune surveillance are typically lacking. This lymphoma would be predicted to be resistant to immune CBT therapy with anti–PD-1 or anti–PD-L1 antibodies. (B) An inflamed lymphoma environment. This lymphoma environment is enriched in infiltrating immune cells, including CD4⁺ and CD8⁺ T cells. Oncogenic signaling pathways that may promote an inflammatory lymphoma environment, such as NF-κB and NOTCH, are shown. In response to selective pressure from an ongoing antilymphoma immune response, the lymphoma cells have acquired genetic alterations that enhance expression of PD-L1/2 and that lead to defective antigen presentation to T cells. This lymphoma has also recruited numerous TAMs. As such, this lymphoma would be expected to be susceptible to immunotherapy with PD-1 or PD-L1 blockade therapy, and might also be more responsive to immunotherapy with antibodies that block CD47/SIRPα interactions.