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Effects of concomitant and sinecomitant immunity on postsurgical metastasis in mice
Abstract:
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.
Insights
The presence of a primary tumor can inhibit metastasis through specific and nonspecific mechanisms. Removing the primary tumor may increase metastasis, suggesting combined immunotherapy is needed post-surgery.
Area of Science:
- Oncology
- Immunology
- Cancer Metastasis
Background:
- The regulation of metastatic outgrowth is influenced by antitumor resistance mechanisms.
- Methylcholanthrene (MCA)-induced tumors in mice provide a model to study these processes.
Purpose of the Study:
- To assess the role of concomitant and sinecomitant antitumor resistance in regulating metastatic outgrowth.
- To investigate the impact of primary tumor burden and resection on metastasis.
Main Methods:
- Utilized methylcholanthrene (MCA)-induced tumor variants (MCA-F, MCA-D, MCA-2A) in C3H/HeJ mice.
- Assessed spontaneous and artificially induced lung metastases after primary tumor resection.
- Evaluated the effect of primary tumor size and duration on metastatic inhibition.
Main Results:
- The presence of a primary tumor retarded lung colonization, with inhibition varying by tumor size and duration.
- Concomitant immunity showed antigen-specific inhibition with small tumor burdens and nonspecific inhibition with large burdens.
- Resection of primary tumors could facilitate metastasis, especially larger ones, while smaller resections showed greater inhibition.
Conclusions:
- Concomitant antimetastatic immunity involves both specific (immune-mediated) and nonspecific (non-immunological) mechanisms.
- Specific immunity inversely correlates with primary tumor progression, while nonspecific inhibition increases with tumor growth.
- Adjunctive immunotherapy post-surgery should enhance specific immunity and promote nonspecific resistance to minimize metastasis.