A Study of Type 2 Mediated Immune Responses

Abstract

Within tumors, immune responses strongly influence tumor development and stroma architecture, determining cancer progression. Tumor immune responses may be polarized towards a type 1-like “pro-inflammatory” or a type 2-like “alternative” phenotype, the latter mediated by type 2 cytokines (IL-4, IL-5, IL-9 and IL-13). Type 2 responses are generally thought to be associated with enhanced cancer growth. Whilst the effects of single type 2 cytokines in tumor progression have been extensively studied, the overall role of type 2 responses is far from thoroughly understood. In our study we utilised a unique quadruple IL-4/5/9/13 deficient mouse (T2KO), which features complete genetic depletion of type 2 responses. We assessed how the complete lack of type 2 cytokines affects both tumorigenesis and tumor progression. We showed that the complete lack of type 2 responses reduced tumor growth in a mouse model of transplantable breast carcinoma, correlating with improved T cell tumor infiltration and type 1 polarization. We further demonstrated that T cell depletion abolished the protective effects. Thus we formally demonstrated that type 2 responses promote tumor growth. Surprisingly, in carcinogen-driven tumor formation, lack of type 2 responses significantly increased tumor incidence. This was associated with a decreased protective fibrotic encapsulation of the carcinogen, matching pioneering studies on the protective effects of foreign body responses in carcinogenesis. The lack of carcinogen encapsulation in T2KO mice led to enhanced carcinogen spreading, thus suggesting that type 2 responses are protective against carcinogenesis. These findings further suggested a possible protective role against carcinogenesis of enhanced type 2 responses, such as in cases of allergy or asthma. To verify this, we examined two human patient cohorts, in Norway and Italy, and confirmed that, in men, pre-existing type 2 immune responses are significantly associated with reduced incidence of lung cancer. In summary, our findings suggest a protective role of type 2 responses from carcinogenesis, which may become detrimental in cancer progression. Our data also pose novel questions about the influence of immune responses on tumor formation, tumor growth and on tumor-associated fibrosis, occurring at different stages of the disease