The Batlle Lab

PODCAST: Conversaciones del Premio Nobel
Producida por Nobel Prize Outreach y la @fundacionareces.bsky.social, los podcast de la serie "Conversaciones del Premio Nobel " proponen acercar a la sociedad española los logros de estos científicos y sus historias personales.

TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages - Nature Genetics Targeting TGFBR1 in transplantable mouse colorectal tumor organoids improves response to anti-PD-L1 therapy. Mechanistically, TGF-β abrogates clonal expansion of T effector and memory phenotypes and i...

1/17 🧵
🙌Thrilled to share our first hard-core immunology paper out today in Nature Genetics! 👇

➡️We unravel how TGFβ suppresses the innate and adaptive immune system in microsatellite stable colorectal cancer (MSS CRC).

Very proud of the team and efforts behind it.

www.nature.com/articles/s41...

Our recent Cancer Discovery study (Centonze et al.) shows that within hours, metastatic CRC cells switch from an EMP1⁺ invasive state to an LGR5⁺ stem-like program, highlighting that Plasticity is a dynamic, regulated cell-state decision

#Bluetorial below👇🏼

#KRAS #Plasticity #ColorectalCancer

⏳Countdown to the 14th #CNAGSymposium!
🗣️Don’t miss Dr. Eduard Batlle from @irbbarcelona.org (@icreacommunity.bsky.social), sharing his insights on “Plasticity, therapy resistance, and immune evasion in metastatic colorectal cancer”

🗓️Dec 16, BCN
📎 www.cnag.eu/events/14th-...
@batllelab.bsky.social

Likewise!!!! 🙌🏼

🧵1/17

📣Thrilled to share our latest study just out in Cancer Discovery!

➡️
aacrjournals.org/cancerdiscov...

🔬 #ColorectalCancer evades #immunotherapy using a dual barrier:

A study by #IRBBarcelona & @cnag-eu.bsky.social reveals how metastatic colorectal tumours block the immune system through two complementary mechanisms.

📰 @natgenet.nature.com

➡️ bit.ly/49BJaC0

#IRBScience @batllelab.bsky.social

🧪

TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages - Nature Genetics Targeting TGFBR1 in transplantable mouse colorectal tumor organoids improves response to anti-PD-L1 therapy. Mechanistically, TGF-β abrogates clonal expansion of T effector and memory phenotypes and i...

17/17

📖 Read the paper: Henriques et al., Nature Genetics

“TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1 macrophages.”
www.nature.com/articles/s41...

➡️Full Text available here: rdcu.be/eOLi6

16/17

This research was supported by the @erc.europa.eu, the Asociación Española Contra el Cáncer (AECC), @caixaresearch.bsky.social , Worldwide Cancer Research, La Marató de TV3, CIBERONC, AGAUR, Fundación Olga Torres, and the Spanish Ministry of Science and Innovation.

15/17

We thank all members of the BatlleLab and our collaborators @irbbarcelona.org & @cnag-eu.bsky.social. Special mention to A. Riera and C. Sanchez for TGFβ inhibitor synthesis. We acknowledge the dedication of technical platforms, the bioinformatic unit, and the animal facility.

14/17
Our work shows that TGFβ coordinates immune suppression across the adaptive and innate compartments, generating a two-layer defense that tumors use to resist immunotherapy.
Breaking this dual barrier — targeting TGFβ alongside PD-1/PD-L1 — can turn CRCs into immunotherapy-sensitive disease

13/17

TGFβ inhibition (via SMIs: galunisertib, LY3200882, or vactosertib) had dramatic effects on these models:
✅ It dismantled the collagen network produced by CAFs
✅It opened the path for peripheral CD8⁺ T cells to enter metastatic lesions
✅It made refractory tumors responsive to aPD-L1 therapy

12/17

We validated these findings in liver metastases generated by mouse tumor organoids carrying 3 or 4 driver mutations (Apc, Kras, Trp53, ±Tgfbr2 or Smad4).

11/17
In the absence of Osteopontin - (Spp1 KO) - metastases remained T cell infiltrated and checkpoint blockade exerted potent therapeutic responses, suggesting therapeutic agents against Osteopontin, could be tested as a proxy for TGFβ inhibition.

10/17

By generating macrophage-specific Tgfbr2 knockout mice, Ana Henriques showed that this population limits T cell proliferation in the TME.

📌Remarkably, we discovered that SPP1 production is necessary for this immunosuppressive macrophage response.

9/17

In parallel, single-cell profiling of the myeloid compartment revealed that TGFβ instructs an immunosuppressive macrophages population characterized by the expression of SPP1 (osteopontin).

8/17
Meanwhile, aPD-L1 did something remarkable but incomplete: it boosted T cell motility allowing infiltrated cells to move and engage targets.
TGFβ inhibition enabled their entry but not their movement.

✅Only combination therapy achieved both, unleashing a fully active antitumor immune response

7/17

In experimental models of advanced colorectal cancer (CRC), we showed that TGFβ signaling on T cells prevented the influx of memory-like T cells from the lymph nodes into the metastatic TME.

🔴Without TGFβ inhibition, the number of T cells is insufficient to eradicate metastatic disease.

6/17

@hoheyn.bsky.social and @paulanietog.bsky.social identified diverse CD8⁺ T cell states — from naïve-like and progenitor to effector and exhausted — and together with Maria Salvany-Celades, they traced how TGFβ inhibition restores clonal expansion and effector differentiation.

5/17

To understand the immune landscape at single-cell resolution, @hoheyn.bsky.social and @paulanietog.bsky.social from @cnag-eu.bsky.social led an extensive scRNA-seq + TCR-seq analysis of tumor-infiltrating lymphocytes (TILs) and myeloid cells in models of metastatic CRC under treatment.

TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis - Nature A combination of TGFβ inhibition and checkpoint-inhibition therapy provokes a potent cytotoxic response against metastatic tumours derived from colorectal cancers in mice.

4/17

We had shown that TGFβ inhibition in CRC enabled T cell infiltration & synergized with immune checkpoint blockade to eradicate metastases 👇.
www.nature.com/articles/nat...

➡️Now we dove into the immunology of metastatic disease: how does TGFβ inhibition reshape the immune landscape of mets?

3/
👌A tremendous team effort led by Ana Henriques, Maria Salvany-Celades, & Alejandro Prados in the BatlleLab, in collaboration with @paulanietog.bsky.social and @hoheyn.bsky.social, with the help of amazing multidisciplinary teams at @irbbarcelona.org, and @cnag-eu.bsky.social.

Kudos to all 🔝🔝🙌🙌

TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages - Nature Genetics Targeting TGFBR1 in transplantable mouse colorectal tumor organoids improves response to anti-PD-L1 therapy. Mechanistically, TGF-β abrogates clonal expansion of T effector and memory phenotypes and i...

2/17
Through genetic dissection in model systems of advanced CRC, integrated single-cell profiling, and analyses of patient data, we reveal that TGFβ builds a dual immune barrier that blocks both the recruitment and expansion of memory T cells in liver metastases.
www.nature.com/articles/s41...

TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages - Nature Genetics Targeting TGFBR1 in transplantable mouse colorectal tumor organoids improves response to anti-PD-L1 therapy. Mechanistically, TGF-β abrogates clonal expansion of T effector and memory phenotypes and i...

1/17 🧵
🙌Thrilled to share our first hard-core immunology paper out today in Nature Genetics! 👇

➡️We unravel how TGFβ suppresses the innate and adaptive immune system in microsatellite stable colorectal cancer (MSS CRC).

Very proud of the team and efforts behind it.

www.nature.com/articles/s41...

Could understanding how #cancer cells talk to their neighbours help stop the disease? Johanna Joyce, a regular at #VIBConf, will uncover these new ways to predict, prevent, and treat cancer. Join #THPT25 before 26 Nov and decode the therapies that outsmart cancer: vibbio.tech/3Le9oAr
#tumorbiology

Oncode Annual Conference 2025 | Oncode Institute Registration is closed!There are roadworks, so the public transport route is different from previous years. For up-to-date information, please use Reisplanner | GVB or Plan je reis met het OV en deelv...

At the Oncode Annual Conference 2025. Fantastic Meeting. Thanks for the invite. Catching up with many colleagues and friends.

www.oncodeinstitute.nl/events/oncod...

Registration for Cancer Cell Plasticity closes on Monday 03 November!

Join us online to explore the fundamental mechanisms that control cancer cell plasticity at multiple biological levels:

eacr.org/conference/c...

🙌🏼 What a fantastic meeting this was! Congrats to everyone who contributed! #EESOrgan @events.embo.org

🔝 A huge thank you to the organizers for the invitation, and for putting together such a memorable conference.

📸 A remarkable aspect was seeing together five generations of Clevers’ Lab!!

📣 Last chance to register for the EACR virtual conference on Cancer Cell Plasticity

You’ll gain new insights into fundamental mechanisms controlling cancer cell plasticity as well as innovative approaches to target them

➡️https://eacr.org/conference/cancercellplasticity2025

@helloeacr.bsky.social