Another benefit of dietary fiber The gut microbiome can modulate the immune system and influence the therapeutic response of cancer patients, yet the mechanisms underlying the effects of microbiota are presently unclear. Spencer et al . add to our understanding of how dietary habits affect microbiota and clinical outcomes to immunotherapy. In an observational study, the researchers found that melanoma patients reporting high fiber (prebiotic) consumption had a better response to checkpoint inhibitor immunotherapy compared with those patients reporting a low-fiber diet. The most marked benefit was observed for those patients reporting a combination of high fiber consumption and no use of over-the-counter probiotic supplements. These findings provide early insights as to how diet-related factors may influence the immune response. —PNK

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rβ). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8 + T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8 + Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.

The immunomodulatory nature of lactoferrin (LF) derives from its ability to bridge innate and adaptive immunity in obtaining physiological equilibrium. LF is an attractive molecule for treatment of diseases that compromise immune homeostasis. Oral delivery is a preferable method for LF administration; however, its bioavailability is affected by protein degradation and absorption. The aim of this study was to evaluate the systemic effects of oral and intravenous (IV) administered recombinant human LF (rhLF) on blood cell transcriptome profiling. Rats were administered with a single dose of rhLF by gavage or IV. The transcriptome profiles from control and rhLF-treated rats after 3h, 6h and 24h were analyzed by Clariom D microarray. The results showed differentially expressed genes in response to IV as well as oral administered rhLF including coding and noncoding RNAs. Moreover, a comparison of the differentially expressed genes between oral and IV after 6h revealed that a majority (72.8%) of altered genes in response to oral rhLF administration was common with IV treatment. The pathway profiles showed similarities in up-regulation of specific genes involved in oxidative stress and inflammatory responses for both routes of treatments. These findings provide evidence of the systemic signal transduction effects of orally administered rhLF.

Lung cancer remains the leading cause of cancer death worldwide. Despite the recent advances in cancer treatment, only a subset of patients responds to targeted and immune therapies, and many patients developing resistance after an initial response. Lactoferrin (Lf) is a natural glycoprotein with immunomodulatory and anticancer activities. We produced a novel recombinant human Lf (rhLf) that exhibits glycosylation profile compatible with the natural hLf for potential parenteral therapeutic applications. The aim of this study was to evaluate the anticancer effects of this novel rhLf in human lung adenocarcinoma cells and its mechanisms of action. The results showed a concentration-dependent inhibition of A549 cancer cell growth in response to rhLf. Treatment with 1 mg/ml of rhLf for 24 h and 72 h resulted in a significant inhibition of cancer cell growth by 32% and 25%, respectively. Moreover, rhLf increased fourfold the percentage of early and late apoptotic cells compared to the control. This effect was accompanied by increased levels of caspase-3 activity and cell cycle arrest at the S phase in rhLf-treated cancer cells. Furthermore, rhLf significantly attenuated A549 cell migration. Importantly, treatment of normal human bronchial epithelial (NHBE) cells with rhLf showed the cell viability and morphology comparable to the control. In contrast, chemotherapeutic etoposide induced cytotoxicity in NHBE cells and reduced the cell viability by 40%. These results demonstrate the selective anticancer effects of rhLf against lung adenocarcinoma cells without cytotoxicity on normal human cells. This study highlights a potential for clinical utility of this novel rhLf in patients with lung cancer.

No abstract

No abstract

Agonistic CD40 antibodies have shown promise when used in combination with checkpoint inhibitors in clinical trials for the treatment of malignancies. However, the mechanisms driving antitumor immune responses in patients are not well understood. The aim of this study was to use a preclinical melanoma model to evaluate the impact of intratumoral anti-CD40 administration on treatment efficacy and the tumor immune landscape in the context of systemic anti-PD1 therapy. Mice bearing 8-day established B16 melanoma tumors were injected with CD40 agonist intratumorally, either alone or in combination with anti-PD1 Ab, every 3 days for a total 4 doses. All mice treated with the combination therapy exhibited tumor growth arrest while progressive tumor growth was observed in control mice and mice treated with anti-PD1 alone. At day 15, tumor weights were 7- and 3-fold reduced in mice treated with the combination therapy as compared to control IgG or PD1 monotherapy, respectively. CyTOF analysis showed a 4-fold increase in the frequency of tumor-infiltrating immune cells in mice treated with either CD40 agonist alone or the combination therapy. Interestingly, CD40 agonistic Ab selectively expanded CD8+ T cells and the combination therapy exhibited a more pronounced effect compared to treatment with anti-PD1 Ab alone. Moreover, CD39+ CD8 T cells, representing tumor antigen-specific cytotoxic T cells, were 14- and 3-fold higher in tumors from mice treated with the combination therapy as compared to control or PD1-treated mice, respectively. This effect correlated with increases in the frequency of antigen-presenting cells, including cDC1 (6-fold) and B cells expressing CD40 (3-fold) in response to the combination therapy. In addition, the combination therapy significantly decreased myeloid cell population resulting in an 8-fold reduction in the ratio of myeloid cells to T cells. Amongst myeloid cells, the density of the monocytic population was diminished, with a selective 10-fold reduction of CD206+ M2-macrophages in tumors from mice treated with both Abs. Our findings provide evidence that combining systemic anti-PD1 therapy with intratumoral CD40 agonist enhanced antitumor immune responses by selectively expanding tumor antigen-specific effector CD8+ T cells, which was associated with increased infiltration of antigen-presenting cells and attenuation of immunosuppressive myeloid cells. Citation Format: Barbara Pazdrak, Heather M. Sonnemann, Salah-Eddine Bentebibel, Barbara M. Nassif, Greg Lizee, Adi Diab. Intratumoral CD40 agonist enhances the antitumor effect of anti-PD1 immunotherapy by activation of antigen-presenting cells and selective expansion of effector CD8+ T cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5079.

Obesity is associated with an increased risk and progression in a variety of cancers. In melanoma, obesity is associated with an increased risk of recurrence following surgical resection which may reflect immune escape of cancer surveillance. We sought to examine the impact of obesity on antitumor immunity in an immunogenic preclinical melanoma model.Male C57/Bl6 mice were fed a 45% fat diet or 10% fat diet for 12 months resulting in obese (body weight 52.8g ±1.3) vs control mice (body weight 38.8g ±2.2). For these studies, we utilized the YUMMER cell line, a C57BL/6J syngeneic melanoma cell line with three driver mutation/deletions (BrafV600E, Pten-/-, Cdkn2a-/-), irradiated to mimic the high mutation burden of human melanoma. 0.5x106 YUMMER cells were subcutaneously injected into the flank of aged (13 month old) control and obese mice. After 14 days post injection, tumors in control mice either had growth arrest or regression. In contrast, all obese mice exhibited progressively growing tumors with 6-fold greater tumor weights after 21 days as compared to control (1.3g ±0.4 vs 0.23g ±0.06). CyTOF analysis of tumor-infiltrating immune cells at day 21 showed 2-fold decrease in the percentage of CD4 T cells in tumors from obese mice (9.8% vs 21.1% of CD45). In addition, obesity resulted in 4-fold increase in the frequency of intratumoral Treg (26.1% vs 8.3% of CD3CD4 cells) and CD8/Treg ratio was 2-fold reduced in obese mice. In contrast to prior findings in obese mice bearing B16 melanomas, the percentage of CD8 T cells expressing PD1 was similar (80.4% vs 74.3%), but we found 2-fold higher frequency of CD8PD1 T cells co-expressing TIM3 and LAG3 in tumors from obese mice (43.3% vs 23.0%). Moreover, obesity also attenuated the frequency of tumor-infiltrating cDC2 (1.4% vs 3.5% of CD45) but did not affect NK cells or B cell proportions. Furthermore, the ratio of tumor infiltrating myeloid cells to T cells was higher in obese mice (1.94:1 vs 0.82:1). Moreover, myeloid cells from obese mouse tumors had higher expression of PDL1, CD206, and CD38 markers.Our findings provide evidence that obesity impairs antitumor immunity by modulating the relative abundance of intratumoral immune cell populations and their phenotypes to promote immunosuppressive microenvironment. These findings will be validated in subsequent studies and examined in human specimens. Citation Format: Barbara Pazdrak, Duncan Mak, William Damsky, Marcus Bosenberg, Brooklyn Lochmann, Matthew Gubin, Jennifer McQuade. Obesity-induced impairment of antitumor immunity is associated with an immunosuppressive tumor immune landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 70.