The role of concomitant and sinecomitant antitumor resistance 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 spontaneous lung
metastasis and expression of parental
tumor-specific
transplantation antigens. The incidence of spontaneous lung
metastases after 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
metastases. Greater concomitant immunity leading to a reduced number of artificial
metastases 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 (P less than 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. Specific 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
metastases occurred after resection of 7- or 14-day
neoplasms compared to larger
tumors (P less than 0.001 or 0.05). Sinecomitant inhibition is
antigen specific, probably representing an extension of specific concomitant immunity. These results suggest that adjunctive immunotherapeutic protocols for surgically treated hosts should augment existent specific immunity and promote nonspecific resistance, in order to minimize metastatic outgrowth.