MHC Class I Expression in Experimental Mouse Models of Cancer: Immunotherapy of Tumors with Different MHC-I Expression Patterns

Abstract

In this chapter, we analyze the role of tumor MHC-I cell surface expression in the success of various types of cancer immunotherapy in several mouse models of cancer. First, we show how different immunotherapies influence the growth of MHC-I-positive or -deficient primary tumors. We also describe how MHC-I expression on primary tumors determine the success of immunotherapy in control of metastatic progression. Finally, we support the role of tumor MHC-I cell surface expression in success of immunotherapy against metastatic disease, by describing our recent results obtained from a murine fibrosarcoma model, a heterogeneous tumor composed of various tumor cell clones with different MHC-I expression. We performed spontaneous metastasis assays with different cell clones derived from a primary fibrosarcoma tumor induced by methylcholanthrene (MCA) in BALB/c mice. These fibrosarcoma clones have distinct patterns of MHC-I cell surface expression, ranging from MHC-I-negative to MHC-I-highly positive expression. Each clone has different spontaneous metastatic capacity, which correlates directly with its MHC-I cell surface expression. Clones with high MHC-I expression demonstrated high spontaneous metastatic capacity. Two types of immunotherapy, chemotherapy alone, and chemo-immunotherapy, were applied separately to treat spontaneous metastatic colonization generated by the different fibrosarcoma clones. The results showed that the success of the immunotherapy against metastatic disease depends on MHC-I cell surface expression on fibrosarcoma cells. Spontaneous metastatic capacity presented by a highly positive MHC-I fibrosarcoma clone was completely abrogated by immunotherapies and chemo-immunotherapy. In contrast, metastatic disease derived from a fibrosarcoma clone with intermediate MHC-I levels was only partially inhibited. These results indicate that MHC-I cell surface expression in primary tumor may be crucial for the success of immunotherapy against metastatic disease.