Fredrik Schjesvold

How Do CD4+ T Cells Detect and Eliminate Tumor Cells That Either Lack or Express MHC Class II Molecules?

CD4+ T cells contribute to tumor eradication, even in the absence of CD8+ T cells. Cytotoxic CD4+ T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4+ T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4+ T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR) transgenic models, where anti-tumor responses of naïve CD4+ T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCIIPOS and MHCIINEG tumors, presentation of tumor-specific antigen by host antigen-presenting cells (APCs) appears to be required for CD4+ T cell priming. This has been extensively studied in a myeloma model (MOPC315), where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4+ T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCIIPOS and MHCIINEG tumor cells differ. In a TCR-transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-γ stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.

Indirect CD4 + T cell-mediated elimination of MHC II NEG tumor cells is spatially restricted and fails to prevent escape of antigen-negative cells

Tumor‐specific Th1 cells can activate tumor‐infiltrating macrophages that eliminate MHC class II negative (MHC IINEG) tumor cells. Activated M1‐like macrophages lack antigen (Ag) receptors, and are presumably unable to discriminate and thus kill both Ag‐positive (AgPOS) and Ag‐negative (AgNEG) tumor cells (bystander killing). The lack of specificity of macrophage‐mediated cytotoxicity might be of clinical importance as it could provide a means of avoiding tumor escape. Here, we have tested this idea using mixed populations of AgPOS and AgNEG tumor cells in a TCR‐transgenic model in which CD4+ T cells recognize a secreted tumor‐specific antigen. Surprisingly, while AgPOS tumor cells were recognized and rejected, AgNEG cells grew unimpeded and formed tumors. We further demonstrated that macrophage‐mediated cytotoxicity was spatially restricted to areas dominated by AgPOS tumor cells, sparing AgNEG tumor cells in the vicinity. As a consequence, macrophage tumoricidal activity did not confer bystander killing in vivo. The present results offer novel insight into the mechanisms of indirect Th1‐mediated elimination of MHC IINEG tumor cells.

Autologous bone marrow Th cells can support multiple myeloma cell proliferation in vitro and in xenografted mice

Multiple myeloma (MM) is a plasma cell malignancy where MM cell growth is supported by the bone marrow (BM) microenvironment with poorly defined cellular and molecular mechanisms. MM cells express CD40, a receptor known to activate autocrine secretion of cytokines and elicit proliferation. Activated T helper (Th) cells express CD40 ligand (CD40L) and BM Th cells are significantly increased in MM patients. We hypothesized that activated BM Th cells could support MM cell growth. We here found that activated autologous BM Th cells supported MM cell growth in a contact- and CD40L-dependent manner in vitro. MM cells had retained the ability to activate Th cells that reciprocated and stimulated MM cell proliferation. Autologous BM Th cells supported MM cell growth in xenografted mice and were found in close contact with MM cells. MM cells secreted chemokines that attracted Th cells, secretion was augmented by CD40-stimulation. Within 14 days of culture of whole BM aspirates in autologous serum, MM cells and Th cells mutually stimulated each other, and MM cells required Th cells for further expansion in vitro and in mice. The results suggest that Th cells may support the expansion of MM cells in patients.