The therapeutic significance of concomitant antitumor immunity

Summary Intravenous injection of 50 g bacterial endotoxin can cause complete regression of an established SA1 sarcoma, but not if the tumor ir growing in mice that are incapable of generating concomitant immunity because they have been made T cell-deficient by thymectomy and -radiation (TXB mice). It also was shown that endotoxin fails to cause complete regression of a tumor that is either too large or too small. Only when administered on day 9 of tumor growth, at the time of peak concomitant immunity, did endotoxin cause the tumor to undergo complete regression. Direct evidence that the antitumor effect of endotoxin is dependent on concomitant immunity consisted in the demonstration that an SA1 sarcoma growing in TXB recipients can be primed for endotoxin-induced regression by IV infusion of splenic T cells from concomitantly immune donors bearing an endotoxin-susceptible 9-day tumor. Surprisingly, the donor T cells that primed the recipient tumor for endotoxin-induced regression were of the Ly-1⁺2^– phenotype, as evidenced by their susceptibility to treatment with anti-Ly-1 antibody and complement, and their complete resistance to treatment with anti-Ly-2 antibody and complement. They were different, therefore, from the T cells that cause the regression of smaller tumors in -irradiated recipients without the aid of endotoxin. It is suggested that the antitumor function of endotoxin depends on its ability to cause intratumor macrophages to acquire and express tumoricidal function, but only after the macrophages have been activated by Ly-1⁺2^– tumor-sensitized T cells.     

Impairment of systemic concomitant antitumor immunity by excess soluble tumor antigen

Summary Animals bearing a 3-methylcholanthrene induced sarcoma called MC1 rejected substantial numbers of a suspension of the same tumor cells injected IV in comparison with normal rats. The factors that protected the host against lung metastases were impaired by the administration of tumor antigen in the form of irradiated tumor cells or soluble tumor antigen. Animals bearing an MC1 tumor which received either unrelated MC11 irradiated tumor cells or soluble tumor antigen had more lung metastasis than the animals not given any tumor products. However, a statistically significant increase in the number of lung tumor nodules was observed in the rats treated with MC1, compared with those treated with MC11 tumor antigen (soluble tumor antigen or irradiated tumor cells) or no tumor antigen. The increase in the outgrowth of lung tumor nodules in the tumor-bearing host given an excess of tumor materials was produced by a dual mechanism of inhibition of the concomitant immune resistance and nonspecific resistance. The present study shows that soluble tumor antigen similar to material shed from a primary tumor is able to impair concomitant immune resistance to tumor cells within the lungs.     

Suppression of generation of concomitant antitumor immunity by passively transferred suppressor T cells from tumor-bearing donors

Summary Infusion of normal recipient mice with suppressor T cells from donors bearing a progressive Meth A fibrosarcoma results in a diminished capacity of the recipients to generate concomitant and postexcision antitumor immunity. The passive transfer of suppressor cells which prevented the generation of immunity to the Meth A fibrosarcoma did not affect the capacity of the recipients to reject an allogeneic tumor. The data provides direct evidence in support of the hypothesis that suppressor T cells, generated at later stages of growth of Meth A fibrosarcoma, function to down-regulate an already acquired mechanism of concomitant immunity.This work was supported by Grants CA-16642 and CA-17794 from the National Cancer Institute, Grant RR-05705 from the Division of Research Resources, NIH, and a grant from R. J. Reynolds Industries, Inc     

Treatment with Imiquimod enhances antitumor immunity induced by therapeutic HPV DNA vaccination

Background

There is an urgent need to develop new innovative therapies for the control of advanced cancer. The combination of antigen-specific immunotherapy with the employment of immunomodulatory agents has emerged as a potentially plausible approach for the control of advanced cancer.

Methods

In the current study, we explored the combination of the DNA vaccine encoding calreticulin (CRT) linked to human papillomavirus type 16 (HPV-16) E7 antigen (CRT/E7) with the TLR7 agonist imiquimod for their ability to generate E7-specific immune responses and antitumor effects in tumor-bearing mice.

Results

We observed that treatment with CRT/E7 DNA in combination with imiquimod leads to an enhancement in the E7-specific CD8+ T cell immune responses and a decrease in the number of myeloid-derived suppressor cells in the tumor microenvironment of tumor-bearing mice. Furthermore, treatment with CRT/E7 DNA in combination with imiquimod leads to significantly improved antitumor effects and prolonged survival in treated mice. In addition, treatment with imiquimod led to increased number of NK1.1+ cells and F4/80+ cells in the tumor microenvironment. Macrophages and NK1.1+ cells were found to play an important role in the antitumor effects mediated by treatment with CRT/E7 DNA in combination with imiquimod.

Conclusions

Thus, our data suggests that the combination of therapeutic HPV DNA vaccination with topical treatment with the TLR7 agonist imiquimod enhances the antitumor immunity induced by DNA vaccination. The current study has significant implications for future clinical translation.

     

The role of cellular proteostasis in antitumor immunity

Immune checkpoint blockade therapy is perhaps the most important development in cancer treatment in recent memory. It is based on decades of investigation into the biology of immune cells and the role of the immune system in controlling cancer growth. While the molecular circuitry that governs the immune system in general—and antitumor immunity in particular—is intensely studied, far less attention has been paid to the role of cellular stress in this process. Proteostasis, intimately linked to cell stress responses, refers to the dynamic regulation of the cellular proteome and is maintained through a complex network of systems that govern the synthesis, folding, and degradation of proteins in the cell. Disruption of these systems can result in the loss of protein function, altered protein function, the formation of toxic aggregates, or pathologies associated with cell stress. However, the importance of proteostasis extends beyond its role in maintaining proper protein function; proteostasis governs how tolerant cells may be to mutations in protein-coding genes and the overall half-life of proteins. Such gene expression changes may be associated with human diseases including neurodegenerative diseases, metabolic disease, and cancer and manifest at the protein level against the backdrop of the proteostasis network in any given cellular environment. In this review, we focus on the role of proteostasis in regulating immune responses against cancer as well the role of proteostasis in determining immunogenicity of cancer cells.     

Preexisting antitumor immunity augments the antitumor effects of chemotherapy

Efficacy of cancer chemotherapy is generally believed to be the result of direct drug killing of tumor cells. However, increased tumor cell killing does not always lead to improved efficacy. Herein, we demonstrate that the status of antitumor immunity at the time of chemotherapy treatment is a critical factor affecting the therapeutic outcome in that tumor-bearing mice that possess preexisting antitumor immunity respond to chemotherapy much better than those that do not. Enhancing antitumor immunity before or at the time of chemotherapy-induced antigen release increases subsequent response to chemotherapy significantly. By in vitro and in vivo measurements of antitumor immunity, we found a close correlation between the intensity of antitumor immunity activated by chemotherapy and the efficacy of treatment. Immune intervention with interleukin-12 during the early phase of chemotherapy-induced immune activation greatly amplifies the antitumor response, often resulting in complete tumor eradication not only at the chemo-treated local site, but also systemically. These findings provide additional evidence for an immune-mediated antitumor response to chemotherapy. Further, our results show that timely immune modification of chemotherapy-activated antitumor immunity can result in enhanced antitumor-immune response and complete tumor eradication.     

Induction of antitumor immunity by indomethacin

Irradiated tumor cells given, together with indomethacin, to syngeneic mice induced an antitumor response and conferred protection against a challenge of a lethal dose of murine mammary (4T1) and lung (3LL) carcinoma cells. Continuous administration of indomethacin was crucial throughout the entire period of immunization and challenge, as no protection was achieved when the drug was given during only one of these procedures. Antitumor immunity was long-lasting and, when tested in the 4T1 model, 48% of mice were resistant to a second challenge of lethal tumor cells. Tumor-free immune mice that were given indomethacin for more than 300 days remained healthy with normal white blood cell counts and normal spleen size. Cells isolated from immune mice were able to kill tumor cells in culture after in vitro activation by interleukin-2, in a manner similar to cells from naive normal control mice. In addition, the mitogenic response of their T cells was as high as that of the control naive mice. While indomethacin was able to induce antitumor immunity to 4T1 and 3LL murine carcinoma cells, both of which contain a high concentration of endogenic prostaglandin E₂ (PGE2), no such immunity was achieved to murine tumor cells with a low concentration of endogenic PGE2. These results suggest a correlation between PGE2 concentration and the ability of indomethacin to induce antitumor immunity. We therefore suggest that an immunotherapy protocol with long-term dispensation of a tolerable dose of an immunomodulator, given together with irradiated autologous tumor cells, may stimulate antitumor responses to tumors containing high concentrations of endogenic PGE2. Received: 12 August 1999 / Accepted: 21 September 1999     

The potential for enhancing the therapeutic efficacy of antitumor preparations

Joint introduction of cytostatic antitumor drugs and dogfish liver extract into animals with experimental tumors was shown to increase the efficacy of drugs as revealed by the increase in life span of experimental animals.     

The antimetastatic effect of macrophages restored by indomethacin: concomitant tumor immunity model

The role of macrophages acting as immunologic antitumor effectors and promoters of tumor growth are poorly understood as yet. We investigated the role of macrophage in model of concomitant immunity (CI), a phenomenon of secondary tumor rejection during the primary tumor growth. It has been shown that the period of CI weakening can coincide with appearance of tumor metastases. We used mammary carcinoma (MC) artificial lung metastases to evaluate the influence of macrophages from various period of CI on the development of metastases in mice. Our results indicated that macrophages are responsible for the late period of CI weakening and suppression. To investigate weather prostaglandins can mediate suppressive effect of macrophages we used experiments with indomethacin and we found that inhibition of prostaglandin E2 synthesis by indomethacin restored antimetastatic effect of concomitant immune macrophages.     

The influence of cyclophosphamide on antitumor immunity in mice bearing late-stage tumors

Spleen cells from mice bearing late-stage methylcholanthrene-induced tumor did not show any tumor activity when mixed with tumor cells in Winn's assay. Treatment of these mice with cyclophosphamide (CY) induced a tumor-inhibitory activity in spleen, occurring on day 7 after treatment, reaching its maximum on day 11 and disappearing by day 21. This antitumor activity could not be induced in control, tumor-free or T-deficient tumor-bearing mice. CY-induced tumor-inhibitory activity was immunologically specific, and mediated by Thy-1⁺, L3T4^–, Ly-2⁺ cells. Contrary to spleen cells from untreated tumor-bearing mice, spleen cells from CY-treated tumor-bearing mice did not suppress the antitumor activity of immune spleen cells in Winn's assay. However, in contrast to immune spleen cells, CY-induced tumor-inhibitory cells did not manifest antitumor activity when transferred systemically (i. v.) into T-cell-deficient tumor-bearing mice. Even more, spleen cells from CY-pretreated mice, harvested 7–15 days after the drug administration, partially suppressed the antitumor activity of concomitantly transferred spleen cells from specifically immune mice. Nevertheless, CY-pretreated mice manifested concomitant immunity, i.e. these mice exhibited higher resistance to a second inoculum of the same tumor than did nontreated mice or even mice with excised primary tumor.     

The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity

Although iron is required for cell proliferation, iron‐dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron‐mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of iron‐responsive element‐binding protein 2 (IREB2), selectively reduced in colorectal cancer. Clinically, downregulation of OTUD1 is highly correlated with poor outcome of cancer. Mechanistically, OTUD1 promotes transferrin receptor protein 1 (TFRC)‐mediated iron transportation through deubiquitinating and stabilizing IREB2, leading to increased ROS generation and ferroptosis. Moreover, the presence of OTUD1 promotes the release of damage‐associated molecular patterns (DAMPs), which in turn recruits the leukocytes and strengthens host immune response. Reciprocally, depletion of OTUD1 limits tumor‐reactive T‐cell accumulation and exacerbates colon cancer progression. Our data demonstrate that OTUD1 plays a stimulatory role in iron transportation and highlight the importance of OTUD1‐IREB2‐TFRC signaling axis in host antitumor immunity.     

The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer

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