Expression of Class II-MHC Antigens by Tumor-Associated and Peritoneal Macrophages: Systemic Induction During Tumor Growth and Tumor Rejection

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Abstract
It was shown previously that combination therapy of tumor-bearing mice resulted in amplification of antitumor responses at the site of tumor rejection and involved some of the classical components of the immunological network. As a continuation of this work, we now show that amplification of immune responses involves an increase in class II-MHC antigen (Ia) expression both at the tumor site and peripherally in the peritoneal cavity. Of further interest, however, was the observation that there was also an increase in la expression by tumor-associated macrophages (TAM) and peritoneal macrophages (PMs) in mice bearing progressing tumors. In these experiments, Ia expression by TAM and PMs was assessed in C57BL/6J mice bearing the progressing syngeneic MCA/76-9 sarcoma as well as in mice that had received combination therapy consisting of an intraperitoneal injection of cyclophosphamide (CY) and an intravenous injection of tumor-sensitized T lymphocytes (immune cells). When progressing tumors were analyzed, it was seen that by the fourth day after tumor cell implantation, 45–60% TAM expressed la, a level that was sustained throughout the course of tumor growth. The treatment of tumor-bearers with CY had no effect on la expression by TAM. However, the number of la-expressing TAM increased significantly after combination therapy and, as the tumors regressed, reached a peak of up to 100% in the second week after therapy. TAM were shown by Northern blot hybridization to contain mRNA encoding for the laβ chain. When la expression by PMs was assessed, it was seen that during tumor progression there was an increased expression of la over background (from < 10 to about 40%), beginning 9–12 days after tumor cell implantation and continuing for the duration of the experiments. This was not influenced by CY injection. Combination therapy significantly increased the number of PMs expressing la (up to 80%). la expression by PMs could be induced rapidly in vivo by injecting normal B6 mice intraperitoneally (ip) with T cells isolated from tumors induced to regress by combination therapy. PMs isolated up to 15 days after injection were shown to express Ia. Moreover, the ip injection of a mixture of specific MCA/76-9 tumor cells and these tumor-associated lymphocytes resulted in a more rapid rate and a higher level of Ia expression by PMs compared with the level induced by either treatment alone. In contrast to these findings, it was shown that there was little la expression by TAM and PMs from mice bearing the relatively nonimmunogenic sarcoma MCA/77-23. Overall, the data suggest that antitumor immune responses result in a widespread systemic increase in la expression by macrophages.

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