Immunologic Milieu of Mature T-Cell and NK-Cell Lymphomas-Implications for Therapy

T-cells and natural killer (NK) cells share the same ontogeny, and lymphomas derived from them are clinically diverse, occurring in nodal and extranodal sites. In addition to inherent properties of these lymphomas, their microenvironment also impacts on pathogenesis and response to therapy. An understanding of the milieu of T-cell and NK cell lymphomas has important implications on treatment.

Components of the microenvironment include tumour-associated macrophages (TAM), non-neoplastic T-cells and B-cells, eosinophils, dendritic cells, endothelial cells and blood vessels. TAM typically undergoes M2 polarization, promoting angiogenesis and inhibiting anti-tumour cellular immunity. In lymphomas of follicular helper T-cell derivation, increased B-cell proliferation occurs, which may in turn enhance neoplastic T-cell growth. The expression of immune checkpoint ligands on TAM, dendritic cells or lymphoma cells induces an immunosuppressive environment conducive to neoplastic proliferation. Strategies against this complex cellular and immunologic microenvironment have shown promises. These include the use of signal transduction inhibitors, monoclonal antibodies against chemokines or non-neoplastic microenvironmental cells, immunomodulatory drugs and immune checkpoint blockade. As T-cell and NK cell lymphomas are highly heterogeneous, clinical trials to demonstrate efficacy of a given therapeutic approach requires careful design aiming at enriching patient populations who will best respond. Targeting of the immunologic milieu in T-cell and NK-cell lymphomas offers exciting challenges and opportunities.