Re-educating the Tumor Microenvironment in the Clinic

The tumor microenvironment plays a central role in lymphoproliferative disorders and constitution of the microenvironment is associated with patient outcome. Although malignant lymphocytes predominate, cells other than tumor cells are commonly present in malignant lymph nodes. These cells include T lymphocytes, NK cells, dendritic cells and monocytes that seem to be more than simple residual elements from the normal lymph node structure. It is thought that these infiltrating immune cells are part of an antitumor immune response, yet they appear unable to eradicate the malignant clone.

Previous studies have shown however that multiple factors present in the tumor microenvironment oppose an effective antitumor immune response. Cells with suppressive function, including T regulatory cells, myeloid derived suppressor cells and suppressive monocytes, are abundant in lymphoma tissue. Suppressive cytokines such as TGFβ and IL-10 are highly expressed in tumors. Furthermore, intratumoral T-cell exhibit an exhausted phenotype with limited proliferation, cytokine production or cytolytic function. Recent therapeutic approaches have focused on overcoming T-cell suppression by activating T-cells or blocking inhibitory signals, thereby re-educating the suppressive tumor microenvironment.

Clinical trial results with PD-1 and CTLA-4 directed antibodies in both non-Hodgkin lymphoma and Hodgkin lymphoma have been very promising. Overall response rates particularly in Hodgkin lymphoma patients treated with anti-PD-1 antibodies have been remarkable, although complete responses have been uncommon. Current studies are in progress to confirm the initial results, and further trials will assess the efficacy of immune checkpoint blockade in combination with standard therapies.