T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

Abstract

SUMMARY Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8+ cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1+ myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40 and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies.

Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses

“…Our study illustrates that adoptive cell therapy with CTLs increases the frequency of tumor DCs in both WT and Zbtb46 bone marrow chimeras, presumably by augmenting proinflammatory signals in the TME (25). In WT bone marrow chimeras, DC2 and DC3 increased, whereas the frequency of DC1 remained constant.…”

“…As compared with DC1/DC2, DC3 showed a similar capacity to stimulate OT-1 CTLs, suggesting that iNOS expression per se may not reliably predict APC activity and CTL responses in vivo. Interestingly, Marigo et al (25) reported that CTLs stimulate tumor DCs to produce NO, which inhibited tumor growth.…”

“…We speculate that cytokines released in the TME following adoptive cell therapy skews monocyte differentiation toward DC3 rather than to these other cell types. For example, IFN-g released from CTLs and NK cells promotes development of DCs and their production of IL-12, a key driver of CTL cytotoxicity (25,37). In some settings, however, IFN-g may switch monocyte differentiation from DCs to macrophages (38).…”

PEG-<em>b</em>-(PELG-<em>g</em>-PLL) nanoparticles as TNF-&alpha; nanocarriers: potential cerebral ischemia/reperfusion injury therapeutic applications

“…TNF-α, a well-known proinflammatory cytokine present in neurons and the glia, is involved in physiological and pathophysiological processes of the brain. 23,33,37,38 TNF-α acts as an effector molecule in brain development and is often involved in different signaling pathways to elicit the activation of macrophages and glial cells for neurotoxin production and to initiate the apoptosis/ death process in neurons. [39][40][41] Until now, the overall role of α α α α α α α α α α α α Figure 5 The levels of sOD, MDa, Il-4, Il-6, Il-8, Il-10, and NO in the rat brain tissue (n=10).…”

“…[19][20][21] Research shows that TNF-α can prevent the death/apoptosis of neurons by a mechanism involving activation of transcription factor NF-κB, which induces the expression of Mn-SOD and Bcl-2. [22][23][24] The pharmacokinetics of TNF-α is characterized by an extremely short half-life (15-30 min) and low bioavailability. 25,26 Reports have concluded that it is difficult to control the dose of TNF-α preconditioning for treatment of BI/RI, and a large dose of TNF-α can result in significant side effects, including shock and death.…”