PI3Kγ Activates Integrin α4 and Promotes Immune Suppressive Myeloid Cell Polarization during Tumor Progression

Abstract

Immunosuppressive myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) accumulate in tumors where they inhibit T cell-mediated antitumor immune responses and promote tumor progression. Myeloid cell PI3Kg plays a role in regulating tumor immune suppression by promoting integrin a 4 -dependent MDSC recruitment to tumors and by stimulating the immunosuppressive polarization of MDSCs and TAMs. Here, we show that integrin a 4 promotes immunosuppressive polarization of MDSCs and TAMs downstream of PI3Kg, thereby inhibiting antitumor immunity. Genetic or pharmacological suppression of either PI3Kg or integrin a 4 blocked MDSC recruitment to tumors and also inhibited immune suppressive myeloid cell polarization, thereby reducing expression of IL10 and increasing expression of IL12 and IFNg within tumors. Inhibition of PI3Kg or integrin a 4 within tumors stimulated dendritic cell and CD8 þ T-cell recruitment and maturation, as well as tumor cell cytotoxicity in vivo, thereby inhibiting tumor growth. As blockade of PI3Kg or integrin a 4 prevents accumulation of MDSC and reduces myeloid cell expression of immunosuppressive factors that stimulate tumor immune escape, these results highlight PI3Kg and integrin a 4 as targets for the design of cancer therapeutics.

Phosphoinositide 3‐kinase δ is a regulatory T‐cell target in cancer immunotherapy

“…the T‐cell receptor (TCR), the B‐cell receptor, the IL‐2 receptor and various co‐stimulatory receptors, activate p110 δ (hereafter PI3K δ ) upon ligand binding, making it an integral component in mounting a coherent immune response to extracellular cues . PI3K γ is more predominant in myeloid cells and can also play a key role in tumour immune suppression …”

“…12 PI3Kc is more predominant in myeloid cells and can also play a key role in tumour immune suppression. [52][53][54] Dysregulation of PI3Kd signalling leads to altered lymphocyte development and function. 12 Mice with a knockin kinase-inactivating D910A point mutation in p110d (PI3Kd D910A ) have a profound defect in B-cell development and function.…”

The role of myeloid-derived suppressor cells in chronic infectious diseases and the current methodology available for their study

“…In cancer, we can observe this fact during tumor metastasis. In this context, it has been described that tumor progression depends of an incremented MDSCs migration capacity through the expression of CD49d (α4 integrin) . Interestingly, another study described CD49d + MDSCs as highly suppressive but CD49d − MDSCs as poorly suppressive .…”

“…In this context, it has been described that tumor progression depends of an incremented MDSCs migration capacity through the expression of CD49d ( 4 integrin). 143 Interestingly, another study described CD49d + MDSCs as highly suppressive but CD49d − MDSCs as poorly suppressive. 144 Even though it is clear the importance of the micro-environment to guide the expansion of MDSCs, the local environment may be equally important in the amplification of these responses during extreme conditions as sepsis, multisystemic infections, and tumor metastasis.…”

Securing the Payload, Finding the Cell, and Avoiding the Endosome: Peptide‐Targeted, Fusogenic Porous Silicon Nanoparticles for Delivery of siRNA

“…The second therapeutic tested (T‐FNPs) was designed to reprogram tumor‐associated macrophages (TAMs) to inhibit their oncogenic pathways . PI3kγ is a key regulator of immunosuppression, and its downregulation has shown benefits in increasing both CD8+ T‐cell recruitment to the tumor and sensitivity of immunosuppressive myeloid cells to checkpoint inhibitors . In order to target TAMs selectively, we used the LyP‐1 peptide (Table S3, Supporting Information), which homes to TAMs and tumor‐associated lymphatic vessels .…”