Meow
Immune checkpoint blockade (ICB) reactivates T cells to kill tumors and has transformed cancer treatment, but many patients don't respond.
Core trick
Trains a causal intervention model on Perturb-seq knockdowns to rank regulators that push CD4 T cells toward non-responding states.
Description
Immune checkpoint blockade (ICB) reactivates T cells to kill tumors and has transformed cancer treatment, but many patients don't respond. Most work on ICB response has focused on CD8⁺ killer T cells, but emerging evidence shows the CD4⁺ helper T cell is also important. Focusing on CD4⁺ helper T cells, I asked which gene-regulatory pathways push them into a non-responding state, and whether those pathways are druggable. I compared CD4 T cells from responders and non-responders in single-cell RNA-seq of 32 melanoma patients to define a non-responder signature, then integrated a genome-scale Perturb-seq atlas of ~2,600 gene knockdowns in healthy-donor CD4 T cells. Because each knockdown is a direct perturbation, the model learns which regulators causally push cells toward responding or non-responding, not merely what correlates. A model trained on the resting-condition perturbation data reproduced the patient signature well, and the top knockdowns cluster into coherent pathways. The interferon pathway was the highest-ranked controller of the response state, and its downstream genes are upregulated in non-responders — so inhibiting interferon should push cells toward responding. Critically, interferon-receptor antibodies and JAK inhibitors are already-approved interferon-pathway inhibitors, turning the analysis into a concrete, testable hypothesis to sensitize non-responders.
shanshan-yin/Claude-Science-T-cell-pertubseq-melanoma-ICB★ 10 forksHTMLCreated Jul 9, 2026 · last push Jul 16, 2026
README excerpt
# Regulatory pathways of the CD4⁺ T-cell melanoma ICB non-responding state Using single-cell RNA-seq and genome-scale Perturb-seq to find the regulatory pathways in CD4⁺ T cells that drive the melanoma immune-checkpoint-blockade (ICB) **non-responding** state — and to ask whether those pathways are druggable. Immune checkpoint blockade reactivates T cells to kill tumors and has transformed cancer treatment, but many patients don't respond. Most work on ICB response has focused on CD8⁺ killer T cells; emerging evidence shows the CD4⁺ helper T cell is also important. Focusing on CD4⁺ helper cells, we compare responders and non-responders in scRNA-seq of 32 melanoma patients to define a non-responder signature, then integrate a genome-scale Perturb-seq atlas of ~2,600 gene knockdowns in healthy-donor CD4⁺ T cells. Because each knockdown is a **direct perturbation**, the model learns which regulators *causally* push cells toward responding or non-responding — not merely what correlates. ## Explore the results online Interactive, self-contained pages (no install required): - **[Landing page](https://shanshan-yin.github.io/Claude-Science-T-cell-pertubseq-melanoma-ICB/)** — overview and links - **[Full report](https://shanshan-yin.github.io/Claude-Science-T-cell-pertubseq-melanoma-ICB/report.html)** — the 8-panel composite figure with narrative: signature, prediction accuracy, opposing regulatory pathways, and druggable targets - **[Gene explorer](https://shanshan-yin.github.