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Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity [TCRseq]

ABSTRACT: Indications of PD-1/L1- and MAPK-targeted therapies cross cancer histologies. Rationally sequencing and/or combining them may overcome innate and acquired resistance. We observed increased clinical benefit of BRAF andV600MUT/MEK inhibitors in patients with advanced BRAFV600MUT melanoma who were previously treated with immune checkpoint therapy (ICT). To test whether ICT primes MAPK inhibitor (MAPKi) efficacy, we compared sequential/combinatorial regimens in subcutaneous mouse tumors driven by BrafV600, Nras, Nf1 or Kras mutations. The most efficacious regimen consisted of anti-PD-L1 lead-in preceding MAPKi combination and specifically promoted intratumoral pro-inflammatory macrophages and clonal expansion of IFNhi, CD8+ cytotoxic T-cells (relative to CD4+ regulatory T-cells) that highly expressed activation and cytolytic genes. Since melanoma brain metastasis (MBM) and its propensity for therapeutic resistance limit patient survival, we developed an experimental metastasis model of BrafV600MUT MBM. Sequencing anti-PD-L1 before MAPKi combination resulted in superior MBM control and survival as well as robust intratumoral T-cell clonal expansion both intracranially and extracranially. We propose that brief anti-PD-1/L1 dosing prior to MAPKi co-treatment suppresses resistance.

ORGANISM(S): Mus musculus

PROVIDER: GSE177900 | GEO | 2021/08/19

REPOSITORIES: GEO

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Project description:Using both global and conditional knockout mice, we demonstrated that the transcription factor Basic Helix-Loop-Helix Family Member E40 (BHLHE40/DEC1) is required in T cells for rejection of mouse syngeneic tumors upon immune checkpoint therapy (ICT) with anti-PD-1 or anti-CTLA-4 monoclonal antibody (mAb) treatment. Using single cell RNA sequencing (scRNAseq) we profiled intratumoral CD45+ cells from syngeneic mouse sarcomas that (a) grow progressively with control treatment in either Bhlhe40+/+ or Bhlhe40-/- tumor-bearing mice, (b) reject following anti-PD-1 or anti-CTLA-4 ICT in Bhlhe40+/+ tumor-bearing mice, or (c) grow progressively following anti-PD-1 or anti-CTLA-4 in Bhlhe40-/- mice. We performed two separate scRNAseq experiments with the same conditions but harvested tumors on either day 9 post-tumor transplant or day 11 post-tumor transplant. The groups were as follows: (1) Control mAb Bhlhe40+/+, (2) Control mAb Bhlhe40-/-, (3) anti-PD-1 Bhlhe40+/+, (4) anti-PD-1 Bhlhe40-/-, (5) anti-CTLA-4 Bhlhe40+/+, and (6) anti-CTLA-4 Bhlhe40-/-. scRNAseq of intratumoral immune cells in BHLHE40-deficient mice revealed differential ICT-induced immune cell remodeling. These BHLHE40-dependent gene expression alterations were associated with altered metabolism, NF-kB signaling, and IFN- response in subpopulations of intratumoral CD4+ and CD8+ T cells. Intratumoral T cells from tumor-bearing Bhlhe40-/- mice also had higher transcript expression of the inhibitory receptor gene Tigit, along with altered transcript expression of chemokine/chemokine receptor granzyme family members. Bhlhe40-/- CD4+ and CD8+ T cells also had reduced ICT-driven IFN- production. Furthermore, BHLHE40 was required for ICT-induced remodeling of macrophages from a CX3CR1+ CD206+ subpopulation to an iNOS+ subpopulation. While anti-PD-1 or anti-CTLA-4 ICT in tumor-bearing Bhlhe40-/- mice led to tumor outgrowth—several BHLHE40-dependent changes were specific to the ICT treatment that was administered.

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Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity [TCRseq]

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