One of the major limitations of modern cancer vaccine vectors is that, unlike infectious pathogens, to which the immune system has evolved to respond, they are not sufficiently effective in delivering tumor-associated antigens (TAAs) in an immunogenic form to intact professional antigen-presenting cells (APCs) at their anatomic location. To overcome this challenge, we exploited Salmonella Pathogenicity Island 2 (SPI2) and its type III secretion system (T3SS) to deliver a TAA of choice into the cytosol of APCs in situ. We have systematically compared candidate genes from the SPI2 locus of Salmonella typhimurium in the vaccine design, using model antigens and a codon-optimized human TAA, survivin (coSVN). In a screen of 20 SPI2 promoter/effector combinations, the PsifB::sseJ pair demonstrated the maximal potency for antigen translocation in the APC cytosol, presentation to CD8 T cells, and immunogenicity in mice. Therapeutic vaccination with the PsifB::sseJ-coSVN construct (p8032) resulted in CXCR3-dependent tumor infiltration with CD8 T cells, reversal of the CD8:Treg ratio at the tumor site, and potent anti-tumor activity in a CT26 colon carcinoma model. The vaccine’s immunogenicity and anti-tumor potency were further enhanced by co-administration of an NKT-cell ligand, 7WD8-5, which strongly enhanced production of IL-12 and IFNγ in vaccinated mice. Furthermore, therapeutic vaccination with p8032/7WD8-5 resulted in complete tumor regression in an A20 lymphoma model, with the generation of protective memory. Thus, oral antigen delivery via SPI2-encoded T3SS of Salmonella may be the foundation for an effective cancer vaccine platform.

The serine/cysteine protease inhibitor SCCA1 (SERPINB3) is upregulated in many advanced cancers with poor prognosis, but there is limited information about whether it makes functional contributions to malignancy. Here, we show that SCCA1 expression promoted oncogenic transformation and epithelial–mesenchymal transition (EMT) in mammary epithelial cells, and that SCCA1 silencing in breast cancer cells halted their proliferation. SCCA1 overexpression in neu+ mammary tumors increased the unfolded protein response (UPR), IL6 expression, and inflammatory phenotypes. Mechanistically, SCCA1 induced a prolonged nonlethal increase in the UPR that was sufficient to activate NF-κB and expression of the protumorigenic cytokine IL6. Overall, our findings established that SCCA1 contributes to tumorigenesis by promoting EMT and a UPR-dependent induction of NF-κB and IL6 autocrine signaling that promotes a protumorigenic inflammation. Cancer Res; 74(21); 1–12. ©2014 AACR.

The serine/cysteine protease inhibitor SCCA1 (Serpin B3) is upregulated in many advanced cancers with poor prognosis, but there is limited information about whether it makes functional contributions to malignancy. Here we show that SCCA1 expression promoted oncogenic transformation and epithelial-mesenchymal transition (EMT) in mammary epithelial cells, and that SCCA1 silencing in breast cancer cells halted their proliferation. SCCA1 overexpression in neu+ mammary tumors increased the unfolded protein response (UPR), IL-6 expression, and inflammatory phenotypes. Mechanistically, SCCA1 induced a prolonged non-lethal increase in the UPR that was sufficient to activate NF-κB and expression of the pro-tumorigenic cytokine IL-6. Overall, our findings established that SCCA1 contributes to tumorigenesis by promoting EMT and a UPR-dependent induction of NF-κB and IL-6 autocrine signaling that promotes a pro-tumorigenic inflammation.

Colorectal cancer is associated with chronic inflammation and immunosuppression mediated by myeloid-derived suppressor cells (MDSC). Although chemotherapy reduces tumor burden at early stages, it tends to have limited effect on a progressive disease, possibly due to adverse effects on the immune system in dictating disease outcome. Here, we show that patients with advanced colorectal cancer display enhanced MDSC levels and reduced CD247 expression and that some conventional colorectal cancer chemotherapy supports the immunosuppressive tumor microenvironment. A FOLFOX combined therapy reduced immunosuppression, whereas a FOLFIRI combined therapy enhanced immunosuppression. Mechanistic studies in a colorectal cancer mouse model revealed that FOLFIRI-like therapy including the drugs CPT11 and 5-fluorouracil (5FU) damaged host immunocompetence in a manner that limits treatment outcomes. CPT11 blocked MDSC apoptosis and myeloid cell differentiation, increasing MDSC immunosuppressive features and mouse mortality. In contrast, 5FU promoted immune recovery and tumor regression. Thus, CPT11 exhibited detrimental immunoregulatory effects that offset 5FU benefits when administered in combination. Our results highlight the importance of developing therapeutic regimens that can target both the immune system and tumor towards improved personalized treatments for colorectal cancer. Cancer Res; 74(21); 1–14. ©2014 AACR.

Colorectal cancer (CRC) is associated with chronic inflammation and immunosuppression mediated by myeloid-derived suppressor cells (MDSC). Although chemotherapy reduces tumor burden at early stages, it tends to have limited effect on a progressive disease, possibly due to adverse effects on the immune system in dictating disease outcome. Here we show that advanced CRC patients display enhanced MDSC levels, reduced CD247 expression and that some conventional CRC chemotherapy supports the immunosuppressive tumor microenvironment. A FOLFOX combined therapy reduced immunosuppression whereas a FOLFIRI combined therapy enhanced immunosuppression. Mechanistic studies in a CRC mouse model revealed that FOLFIRI-like therapy including the drugs CPT11 and 5FU damaged host immune competence in a manner that limits treatment outcomes. CPT11 blocked MDSC apoptosis and myeloid cell differentiation, increasing MDSC immunosuppressive features and mouse mortality. In contrast, 5FU
promoted immune recovery and tumor regression. Thus, CPT11 exhibited detrimental immunoregulatory effects that offset 5FU benefits when administered in combination. Our results highlight the importance of developing therapeutic regimens that can target both the immune system and tumor in developing improved personalized treatments for CRC.