Uploaded July 2026 | Updated September 2026, 1 hour ago
Why do some lung adenocarcinoma patients respond to immunotherapy and others don't? In this webinar with The Scientist, Olga Anczukow and Ryan Englander show how PacBio long-read RNA sequencing on 12 patient tumors uncovered more than 180,000 high-quality isoforms, over half of them structurally novel, and how a STAT2 intron retention pattern connects splicing directly to atezolizumab response in the OAK trial.
If you've wondered what full-length isoform data could surface in your own tumor cohort, this talk is the long version of the answer.
*Key takeaways*
- Lung adenocarcinoma drives roughly 75,000 U.S. diagnoses a year, with five-year survival near 33%. Better targeting of immunotherapy matters.
- Short-read RNA sequencing misses full-length transcript structure. Long-read sequencing on 12 lung adenocarcinoma tumors produced over 180,000 high-quality isoforms, more than 75% of the isoform count in the current human reference transcriptome, from just 12 tumors.
- More than half of those isoforms were structurally novel, not present in current reference transcriptomes.
- STAT2 has two retained intron events, RI6 and RI12, with different consequences for interferon signaling and STAT2 protein output.
- Antisense oligonucleotides targeting RI6 or RI12 shift STAT2 protein expression and modulate the downstream interferon response in lung adenocarcinoma cells.
- In the OAK trial cohort (503 lung adenocarcinoma patients), the RI12-minus-RI6 high group made up about 15% of the atezolizumab arm and had roughly double the median overall survival of the low group.
- Single-cell and spatial long-read RNA sequencing are the next direction for locating these isoforms inside the tumor microenvironment.
*Featured speakers*
- Olga Anczukow, PhD, Associate Professor, The Jackson Laboratory for Genomic Medicine
- Ryan Englander, MD/PhD Candidate, UConn School of Medicine
*Chapters*
00:00 Alternative splicing in cancer
01:55 Capturing isoforms and predicting drug response
03:24 Why long-read RNA sequencing matters
04:20 Breast cancer examples from the Anczukow lab
05:41 Lung adenocarcinoma and STAT2 intron retention
06:40 Why immunotherapy response matters in lung cancer
08:21 PacBio long-read RNA sequencing on 12 tumors
09:44 Classifying full-length isoforms
10:44 More than half of isoforms are structurally novel
11:17 Interferon signaling, immune evasion, and treatment response
15:15 Novel isoforms enriched for intron retention
17:35 STAT2 RI6 and RI12
19:10 ASOs shift STAT2 splicing and interferon response
21:45 RI6 vs RI12 effects on STAT2 protein
23:28 Can retained introns encode truncated STAT2 proteins?
25:05 AlphaFold predictions and dominant-negative STAT2-RI12
28:50 OAK trial: atezolizumab, docetaxel, and STAT2 splicing
31:18 RI12-minus-RI6 and median survival
32:39 Interferon pathway signals in RI12-high tumors
34:02 Why long-read sequencing was essential
35:53 Next steps: single-cell and spatial long-read RNA sequencing
37:09 Acknowledgments
*Resources*
- The Scientist webinar page: the-scientist.com/long-read-rna-sequencing-reveals-a-regulatory-role-for-splicing-in-immunotherapy-responses-73698
- STAT2 intron retention publication (PacBio summary): pacb.com/publications/intron-retention-regulates-stat2-function-and-predicts-immunotherapy-response-in-lung-cancer
- Preprint (bioRxiv): doi.org/10.1101/2025.08.19.671121
- PacBio cancer transcriptomics: pacb.com/cancer-research/cancer-transcriptomes
*Question for you*
If you could add long-read RNA sequencing to one project in your lab next, which would it be — a tumor cohort, a treatment-response study, or something else? *Comment below.*
Subscribe for more on long-read sequencing in cancer research, immunotherapy biology, and full-length isoform discovery.
For research use only. Not for use in diagnostic procedures.
#PacBio #LongReadSequencing #ImmunotherapyResponse
Why do some lung adenocarcinoma patients respond to immunotherapy and others don't? In this webinar with The Scientist, Olga Anczukow and Ryan Englander show how PacBio long-read RNA sequencing on 12 patient tumors uncovered more than 180,000 high-quality isoforms, over half of them structurally novel, and how a STAT2 intron retention pattern connects splicing directly to atezolizumab response in the OAK trial.
If you've wondered what full-length isoform data could surface in your own tumor cohort, this talk is the long version of the answer.
*Key takeaways*
- Lung adenocarcinoma drives roughly 75,000 U.S. diagnoses a year, with five-year survival near 33%. Better targeting of immunotherapy matters.
- Short-read RNA sequencing misses full-length transcript structure. Long-read sequencing on 12 lung adenocarcinoma tumors produced over 180,000 high-quality isoforms, more than 75% of the isoform count in the current human reference transcriptome, from just 12 tumors.
- More than half of those isoforms were structurally novel, not present in current reference transcriptomes.
- STAT2 has two retained intron events, RI6 and RI12, with different consequences for interferon signaling and STAT2 protein output.
- Antisense oligonucleotides targeting RI6 or RI12 shift STAT2 protein expression and modulate the downstream interferon response in lung adenocarcinoma cells.
- In the OAK trial cohort (503 lung adenocarcinoma patients), the RI12-minus-RI6 high group made up about 15% of the atezolizumab arm and had roughly double the median overall survival of the low group.
- Single-cell and spatial long-read RNA sequencing are the next direction for locating these isoforms inside the tumor microenvironment.
*Featured speakers*
- Olga Anczukow, PhD, Associate Professor, The Jackson Laboratory for Genomic Medicine
- Ryan Englander, MD/PhD Candidate, UConn School of Medicine
*Chapters*
00:00 Alternative splicing in cancer
01:55 Capturing isoforms and predicting drug response
03:24 Why long-read RNA sequencing matters
04:20 Breast cancer examples from the Anczukow lab
05:41 Lung adenocarcinoma and STAT2 intron retention
06:40 Why immunotherapy response matters in lung cancer
08:21 PacBio long-read RNA sequencing on 12 tumors
09:44 Classifying full-length isoforms
10:44 More than half of isoforms are structurally novel
11:17 Interferon signaling, immune evasion, and treatment response
15:15 Novel isoforms enriched for intron retention
17:35 STAT2 RI6 and RI12
19:10 ASOs shift STAT2 splicing and interferon response
21:45 RI6 vs RI12 effects on STAT2 protein
23:28 Can retained introns encode truncated STAT2 proteins?
25:05 AlphaFold predictions and dominant-negative STAT2-RI12
28:50 OAK trial: atezolizumab, docetaxel, and STAT2 splicing
31:18 RI12-minus-RI6 and median survival
32:39 Interferon pathway signals in RI12-high tumors
34:02 Why long-read sequencing was essential
35:53 Next steps: single-cell and spatial long-read RNA sequencing
37:09 Acknowledgments
*Resources*
- The Scientist webinar page: the-scientist.com/long-read-rna-sequencing-reveals-a-regulatory-role-for-splicing-in-immunotherapy-responses-73698
- STAT2 intron retention publication (PacBio summary): pacb.com/publications/intron-retention-regulates-stat2-function-and-predicts-immunotherapy-response-in-lung-cancer
- Preprint (bioRxiv): doi.org/10.1101/2025.08.19.671121
- PacBio cancer transcriptomics: pacb.com/cancer-research/cancer-transcriptomes
*Question for you*
If you could add long-read RNA sequencing to one project in your lab next, which would it be — a tumor cohort, a treatment-response study, or something else? *Comment below.*
Subscribe for more on long-read sequencing in cancer research, immunotherapy biology, and full-length isoform discovery.
For research use only. Not for use in diagnostic procedures.
#PacBio #LongReadSequencing #ImmunotherapyResponse
