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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.

Adoptive T cell therapy (ACT) in combination with lymphodepleting chemotherapy is an effective strategy to induce the eradication of tumors, providing long-term regression in cancer patients. Despite that lymphodepleting regimens condition the host for optimal engraftment and expansion of adoptively transferred T cells, lymphodepletion concomitantly promotes immunosuppression during the course of endogenous immune recovery. In this study, we have identified that lymphodepleting chemotherapy initiates the mobilization of hematopoietic progenitor cells that differentiate to immunosuppressive myeloid cells, leading to a dramatic increase of peripheral myeloid-derived suppressor cells (MDSCs). In melanoma and lung cancer patients, MDSCs rapidly expanded in the periphery within 1 week after completion of a lymphodepleting regimen and infusion of autologous tumor-infiltrating lymphocytes (TILs). This expansion was associated with disease progression, poor survival, and reduced TIL persistence in melanoma patients. We demonstrated that the interleukin 6 (IL-6)-driven differentiation of mobilized hematopoietic progenitor cells promoted the survival and immunosuppressive capacity of post-lymphodepletion MDSCs. Furthermore, the genetic abrogation or therapeutic inhibition of IL-6 in mouse models enhanced host survival and reduced tumor growth in mice that received ACT. Thus, the expansion of MDSCs in response to lymphodepleting chemotherapy may contribute to ACT failure, and targeting myeloid-mediated immunosuppression may support anti-tumor immune responses.

The nicotine-derived tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is one of the most potent and abundant procarcinogens found in tobacco and tobacco smoke, and glucuronidation of its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), is an important mechanism for NNK detoxification. In cigarette smokers and tobacco chewers, there is a wide variation in the urinary levels of the ratio of NNAL to NNAL glucuronide (NNAL-Gluc). To determine whether genetic variation plays a potential role in this inter-individual variability, NNAL-glucuronidating activities were analysed in a series of human liver microsomal specimens and compared with UGT2B17deletion genotypes in the same subjects. Assays performed in vitrodemonstrated that over-expressed UGT2B17 exhibits high O-glucuronidating activity against NNAL. When stratifying subjects by UGT2B17genotype, a significant or near-significant decrease in NNAL-O-Gluc formation was observed in liver microsomes from individuals who were either heterozygous (0), P0.07 or homozygous (00), P0.016 for the UGT2B17deletion compared to liver microsomes from individuals with intact UGT2B17alleles (). There was a significant (P<0.01) association between the level of liver microsomal NNAL-O-glucuronide formation and increasing numbers of the UGT2B17null alleles in the liver microsomal specimens examined in this study, and a significant decrease in NNAL-O-Gluc formation was observed when comparing liver microsomes from individuals who had at least one UGT2B17allele deleted (0)(00) versus microsomes from UGT2B17() subjects (P0.004). When stratifying by the median value of NNAL-O-Gluc formation activity, a significantly (P0.015) higher number of subjects with liver microsomes having low NNAL-O-Gluc formation activity contained the UGT2B17null genotype compared to subjects with liver microsomes exhibiting high NNAL-O-Gluc formation activity. When stratifying by UGT2B7UGT2B17 haplotypes, the association between the level of liver microsomal NNAL-O-glucuronide formation and increasing numbers of the UGT2B17null allele was at the level of statistical significance for subjects with the UGT2B7(12) (P0.05) or UGT2B7(22) (P<0.02) genotypes. These data suggest that the UGT2B17deletion polymorphism is associated with a reduced rate of NNAL detoxification in vivoand may increase individual susceptibility to tobacco-related cancers.