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HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.

Vaccines can be a cost effective preventive measure for both primary prevention of disease and prevention of disease recurrence. Several vaccines targeting breast cancer oncodrivers are currently being tested in clinical trials. Whereas clinical response rates to breast cancer vaccines have been modest despite the induction of strong antitumor T cell responses, it is through these approaches that valuable insight and knowledge have been gained about tumor immunology. With the emergence of new immunotherapies, there is renewed excitement for effective breast cancer vaccine development.

Oral lichen planus (OLP) and burning mouth syndrome (BMS) are chronic conditions affecting the oral mucosa characterized by pain and burning sensation. Saliva plays a significant role in the maintenance of physical and functional integrity of normal oral mucosa. Identification of potential "salivary biomarkers" for early diagnosis and/or monitoring of human diseases is being explored. We investigated the soluble forms of innate immune associated proteins CD14 and toll-like receptor-2 in unstimulated whole saliva (UWS) as potential biomarkers for OLP and BMS. Our results suggest that the levels of sCD14 and sTLR-2 in UWS were upregulated in OLP and BMS respectively. In addition, oral epithelial cells in the saliva of patients with OLP and BMS exhibited elevated levels of CD14 mRNA and decreased levels of TLR-2 mRNA. Interestingly, presence of co-existent oral candidiasis nullified these changes.

A zinc containing metalloprotease, 175 kDa collagenase, purified from adult female Setaria cervi showed strong cross-reactivity with sera from putatively immune (PI) individuals (unpublished observation) and induced cytotoxicity to B. malayi L3 larvae and microfilariae by ADCC mechanism [Srivastava Y, Bhandari YP, Reddy MVR, Harinath BC, Rathaur S. An adult 175 kDa collagenase antigen of Setaria cervi in immunoprophylaxis against Brugia malayi. J Helminth 2004;78:347-52]. These preliminary observations suggested the immunoprotective nature of collagenase. To confirm the vaccine potential of this protease, a vaccine trial was conducted in jirds (Meriones unguiculatus) against human filarial parasite B. malayi. The vaccination resulted into a mean protection level of 75.86% and produced high level of protease neutralizing antibodies. Cytokine analysis in immune jirds sera suggested a mixed Th1/Th2 type cellular immune response whereas ELISA, immunoblotting and enzyme antibody inhibition assay revealed the presence of specific anti-collagenase antibodies. Taken together, all these results suggest that S. cervi 175 kDa collagenase could form the basis of an effective molecular vaccine against human lymphatic filariasis.