Effects of Concomitant and Sinecomitant Immunity on Postsurgical Metastasis in Mice1

The role of concomitant and sinecomitant ant ¡tumoresistance in the regulation of metastatic outgrowth was assessed using methylcholanthrene (MCA)-induced tumors in C3H/HeJ mice. Variants of neoplasms MCA-F, MCA-D, and MCA-2A were selected for proclivity for sponta neous lung metastasis and expression of parental tumor-specific trans plantation antigens. The incidence of spontaneous lung métastasesafter resection of a s.c. tumor of clone 9-4, a highly metastatic variant of the MCA-F tumor, was determined by both the size and the duration of neoplastic disease. The coexistence of the primary local tumor retarded lung colonization both from spontaneous and after artificially induced métastases. Greater concomitant immunity leading to a reduced number of artificial métastases after i.v. challenge with clone 9-4 cells was evident in hosts bearing large (1.6 to 1.8 cm) compared to small (0.1 to 0.2 cm) burdens of the nonmetastatic MCA-F (/' < 0.005). Furthermore, i.v. challenge of mice bearing antigenically different tumors revealed that the concomitant inhibition was antigen specific with small tumor burdens, but nonspecific and possibly more efficacious with large tumor burdens. Therefore, concomitant antimetastatic immunity consists of both specific, immune-mediated resistance and nonimmunological mechanisms. Spe cific concomitant immunity decreases inversely with the progression of the primary, while nonimmunological inhibition of metastasis increases during late stages of primary growth. Abrogation of the strong nonspecific concomitant inhibition by resection of the primary tumor may facilitate lung metastasis. On the other hand, significantly greater inhibition of métastasesoccurred after resection of 7or 14-day neoplasms compared to larger tumors (/' < 0.001 or 0.05). Sinecomitant inhibition is antigen specific, probably representing an extension of specific concomitant im munity. These results suggest that adjunctive immunotherapeutic proto cols for surgically treated hosts should augment existent specific immu nity and promote nonspecific resistance, in order to minimize metastatic outgrowth.