Tumor immunoediting consisting of three phases of elimination, equilibrium or dormancy, and escape has been supported by preclinical and clinical data. A comprehensive understanding of the molecular mechanisms by which antitumor immune responses regulate these three phases are important for developing highly tailored immunotherapeutics that can control cancer. To this end, IFN-γ produced by Th1 cells, cytotoxic T cells, NK cells, and NKT cells is a pleiotropic cytokine that is involved in all three phases of tumor immunoediting, as well as during inflammation-mediated tumorigenesis processes. This essay presents a review of literature and suggests that overcoming tumor escape is feasible by driving tumor cells into a state of quiescent but not indolent dormancy in order for IFN-γ-producing tumor-specific T cells to prevent tumor relapse.

Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy.

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Abbreviations: CD, chow diet; DIAMOND, diet-induced animal model of nonalcoholic fatty liver disease; HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; WD, Western diet. AbstractBackground and Aims: Chronic diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) are associated with chronic inflammation. However, controversial reports as to the key cytokines involved in the process of chronic inflammation hinder development of targeted therapies for patients. This is because, chronic inflammatory process cannot be fully understood by studying the mechanisms of the disease in a short-term or isolated fashion. Understanding of the trend of inflammatory cytokines through longitudinal studies could provide a profound insight into the process of disease progression. Methods:We performed a longitudinal analysis of inflammatory cytokines/ chemokines and faecal microbiome dysbiosis associated with the diet-induced progression of NAFLD to HCC in diet-induced animal model of NAFLD comparing males and females, since males show a higher incidence of these diseases than females do. Results:Longitudinal analyses revealed that a transient and timely increase in LIF and TMIP1 was associated with the inhibition of the progression of NAFLD to HCC in females. On the other hand, chronically increasing trends in CCL12, CCL17, CXCL9 and LIX/CXCL5 were associated with the promotion of the progression of NAFLD to HCC in males. Conclusions:We provided empirical evidence that a methodological shift from snapshot observations to longitudinal data collection and analysis can provide a better understanding of chronic liver diseases. K E Y W O R D S chronic inflammation, HCC, longitudinal research, NAFLD, NASH | 469 MIRSHAHI et Al.

Background Although breast cancer mortality is a result of distant recurrences associated with the establishment of tumor dormancy, current clinical practice guidelines recommend a wait and watch approach for tumor recurrences. This is because of our limited understanding of tumor dormancy and insufficient evidence in support of immunological control of tumor dormancy. Methods We used FVBN202 transgenic mice expressing rat neu oncogene in the mammary glands, and their parental FVB strain lacking neu expression. These models allowed the detection of tumor dormancy at distant sites using the rat neu protein as a tumor marker. We also used Ki67 for the detection of the indolent and quiescent types of tumor dormancy. Multicolor flow cytometry was used to detect dormant tumor cells and T cell subsets. Co-culture studies were performed to determine the role of T cells in preventing regrowth of dormant cells. Results We demonstrated that dormant tumor cells were present at the site of primary breast cancer and at distant sites in the lungs and in the liver very early in the course of early stage breast cancer when no distant metastasis was evident. Dormant tumor cells were characterized as neu expressing Ki67− and Ki67low fractions associated with the induction of local immune responses predominated by CD4+ and CD8+ T effector cell subsets. The presence of neu-autoreactive T cells from FVBN202 mice only prevented regrowth of dormant cells. On the other hand, presence of neu-alloreactive anti-tumor T cells in FVB mice prior to tumor challenge resulted in the protection of mice from the dissemination of dormant tumor cells to distant organs. Conclusion Our results suggest that immunotherapeutic targeting of semi-allogeneic mutant neoantigens during tumor dormancy might prevent distant recurrence of the disease.

Conventional APCs that express MHC class II (MHCII) and co-stimulatory molecules include dendritic cells (DCs) and macrophages. Beyond these conventional APCs, immune stimulatory cells have been more recently shown to extend to a class of atypical APCs, composed of mast cells, basophils, and eosinophils. Here, we describe a unique type of APC, Gr1 CD11b cells with a granularity and size characteristic of myeloid cells and with the ability to present Ag for crosspresentation. These cells constitutively express MHCII and the costimulatory molecules, CD80, CD86, and CD40. They do not express pan markers of myeloid DCs (CD11c), plasmacytoid DCs (Ly6C), or macrophages (F4/80), and their frequency is inversely correlated with myeloid-derived suppressor cells (MDSCs) in tumor-bearing mice. Among splenocytes, they are more abundant than DCs and macrophages, and they exhibit antitumor immune stimulatory function at a steady state without further activation, ex vivo. They are also found within the tumor bed where they retain their immune stimulatory function. Our findings suggest the use of these novel APCs in additional preclinical studies to further investigate their utility in APC-based cancer immunotherapies.

Predominant inflammatory immunological patterns as well as the depletion of CD4+ T cells during nonalcoholic fatty liver disease (NAFLD) are reported to be associated with the progression of hepatocellular carcinoma (HCC). Here, we report that an LRP-1 agonistic peptide, SP16, when administered during advanced NAFLD progression, restored the depleted CD4+ T cell population but did not significantly affect the inflammatory immunological pattern. This data suggests that restoration of CD4+ T cells without modulation of the hepatic immunological pattern is not sufficient to prevent HCC. However, SP16 administered early during NAFLD progression modulated the inflammatory profile. Future studies will determine if regulation of the inflammatory immune response by SP16 early in NAFLD progression will prevent HCC.

Breast cancer mortality is due to distant recurrence of the disease as a result of awakening dormant tumor cells that were established by cancer therapies. The mechanisms through which dormant tumor cells are maintained or escape from dormancy, and relapse remain elusive. One such mechanism that may play a role in tumor dormancy maintenance or escape is autophagy; a process important in all cells for the removal of damaged proteins and organelles. Although autophagy is a mechanism of tumor suppression, it also confers stress tolerance that enables tumor cells to survive under adverse conditions. Here, we wanted to determine the role of autophagy in tumor dormancy and sensitivity of dormant tumor cells to immunotherapy, i.e., IFN-gamma treatment. A mouse mammary carcinoma (MMC) cell line was established from the neu over-expressing FVBN202 transgenic mouse. We also used Adriamycin (ADR) for the establishment of chemotherapy-induced tumor dormancy, and blocked autophagy by chloroquine (CQ). We demonstrated that a transient blockade of autophagy by CQ during ADR treatment prolonged tumor dormancy, in vitro, but not in vivo. Also, we determined that dormant tumor cells established by ADR or ADR+CQ were more sensitive to IFN-gamma induced apoptosis compared with non-dormant, proliferating tumor cells. These observations suggest that autophagy could participate, in part, in tumor dormancy without affecting the sensitivity of dormant cells to IFN-gamma treatment.