Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4+Foxp3− Cell–Mediated Modulation of CD103+ Dendritic Cells

Abstract

Immunotherapy is widely accepted as a powerful new treatment modality for the treatment of cancer. The most successful form of immunotherapy to date has been the blockade of the immune checkpoints PD-1 and CTLA-4. Combining inhibitors of both PD-1 and CTLA-4 increases the proportion of patients who respond to immunotherapy. However, most patients still do not respond to checkpoint inhibitors, and prognostic biomarkers are currently lacking. Therefore, a better understanding of the mechanism by which these checkpoint inhibitors enhance antitumor immune responses is required to more accurately predict which patients are likely to respond and further enhance this treatment modality. Our current study of two mouse tumor models revealed that CD4þ

Dendritic Cells and Their Roles in Anti-Tumour Immunity

“…Single cell mass spectrometry analyses of PBMC from patients with advanced melanoma, before and after anti-PD-1 therapy revealed that CD141 and CD11c, both expressed by cDC1 are strong predictive biomarkers of clinical response to anti-PD-1 treatments [122]. This is consistent with several mouse studies reporting that cDC1-deficient mice do not respond to immune checkpoint blockade using anti-PD-L1 or a combination of anti-PD-1 anti-CTLA4 mAb [123,124]. Furthermore, mice that possess cDC1 defective in antigen crosspresentation fail to establish CTL responses and do not respond to anti-PD-1 blockade [125].…”

Tissue‐specific tumor microenvironments influence responses to immunotherapies

“…After 30‐ to 45‐min digestion at 37 °C, cells were filtered twice (70 μm) and erythrocytes were lysed with ACK (ammonium–chloride–potassium) buffer. For detection of IFNγ production by T cells and NK cells ex vivo, TILs were stimulated with PMA/ionomycin in the presence of GolgiPlug (BD Pharmingen, Franklin Lakes, NJ, USA) and GolgiStop (BD Pharmingen) as described previously . Samples were incubated with fluorescently conjugated antibodies in 2.4G2 Fc blocking antibody.…”

“…For detection of IFNc production by T cells and NK cells ex vivo, TILs were stimulated with PMA/ionomycin in the presence of GolgiPlug (BD Pharmingen, Franklin Lakes, NJ, USA) and GolgiStop (BD Pharmingen) as described previously. 64 Samples were incubated with fluorescently conjugated antibodies in 2.4G2 Fc blocking antibody. Fixable yellow (Invitrogen) was used to determine viable cells.…”

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

“…Specifically, dysfunctional CD4 + T cells appear to express higher levels of CTLA4 at late time points in their activation cycle than their CD8 + counterparts. This may partially explain why, in many murine cancer models, ICB with anti‐CTLA4 alone or in combination with anti‐PD1 induces the expansion of a T H 1‐like subset of CD4 + T cells 73,74 . Whether this expansion is the result of a “rescue” of dysfunctional CD4 + T cells or the priming of novel clonotypes requires further investigation.…”

“…This may partially explain why, in many murine cancer models, ICB with anti-CTLA4 alone or in combination with anti-PD1 induces the expansion of a T H 1-like subset of CD4 + T cells. 73,74 Whether this expansion is the result of a "rescue" of dysfunctional CD4 + T cells or the priming of novel clonotypes requires further investigation. Combination treatments employing NeoAg vaccines and ICB will likely yield optimal responses by overcoming exhaustion of newly primed clones.…”