Right program could turn immune cells into cancer killers

Date:
September 21, 2021
Source:
Johns Hopkins Medicine
Summary:
Cancer-fighting immune cells in patients with lung cancer whose
tumors do not respond to immunotherapies appear to be running on
a different 'program' that makes them less effective than immune
cells in patients whose cancers respond to these immune treatments,
suggests a new study.



FULL STORY ========================================================================== Cancer-fighting immune cells in patients with lung cancer whose tumors
do not respond to immunotherapies appear to be running on a different
"program" that makes them less effective than immune cells in patients
whose cancers respond to these immune treatments, suggests a new study led
by researchers at the Johns Hopkins Kimmel Cancer Center Bloomberg~Kimmel Institute for Cancer Immunotherapy.


==========================================================================
The findings, published in the August 5 issue of Nature, could lead to
new ways to overcome tumor resistance to these treatments.

"Cancer immunotherapies have tremendous promise, but this promise
only comes to fruition for a fraction of patients who receive them,"
says study leader Kellie N. Smith, Ph.D., assistant professor of
oncology and Johns Hopkins Bloomberg~Kimmel Institute of Immunotherapy investigator. "Understanding why patients do or don't respond could help
us raise these numbers." Cancer immunotherapies have gained traction
in recent years as a way to harness the immune system's inherent drive
to rid the body of malignant cells, Smith explains. One prominent type
of immunotherapy, known as checkpoint inhibitors, breaks down molecular defenses that allow cancer cells to masquerade as healthy cells, enabling immune cells known as CD8 T cells to attack the cancer cells.

Different populations of these immune cells recognize specific aberrant proteins, which prompt them to kill malignant cells as well as cells
infected by various viruses.

Although checkpoint inhibitors have shown tremendous success in some
cancer types -- even sometimes eradicating all evidence of disease --
the portion of patients with these dramatic responses is relatively
low. For example, only about a quarter of patients with non-small cell
lung cancer (NSCLC) have significant responses to these treatments.

Searching for differences between responders and nonresponders, Smith and
her colleagues turned to results of a previous immunotherapy study. They gathered blood, tumor and healthy tissue samples taken from 20 early-stage NSCLC patients who took part in the previous study, which tested the
effects of administering immune checkpoint inhibitors before surgery to
remove tumors.

Nine of the patients had a dramatic response to checkpoint inhibitors,
with 10% or less of their original tumors remaining at the time of
surgery. The other 11 patients were nonresponders and had either
significantly lower responses or no response at all.

After isolating CD8 T cells from each of these samples, the researchers
used a technology developed at Johns Hopkins called MANAFEST (Mutation Associated NeoAntigen Functional Expansion of Specific T cells) to search specifically for those cells that recognize proteins produced by cancerous mutations (known as mutation-associated neoantigens, or MANA), influenza
or Epstein-Barr, the virus that causes infectious mononucleosis. They
then analyzed these cells using a commercially available technique called single cell transcriptomics to see which genes were actively producing
proteins in individual cells -- the "program" that these cells run on.

The researchers found that responders and nonresponders alike had
similarly sized armies of CD8 T cells in their tumors, with similar
numbers of cells in both populations that respond to MANA, influenza
and Epstein-Barr. However, when they compared the transcriptional
programs between responders and nonresponders, they found marked
differences. MANA-oriented CD8 T cells from responders showed
fewer markers of exhaustion than those in nonresponders, Smith
explains. Responders' CD8 cells were ready to fight when exposed to
tumor proteins and produced fewer proteins that inhibit their activity,
she says. In one patient who showed a complete response to checkpoint inhibitors -- no evidence of active cancer by the time of surgery -- the MANA-oriented CD8 T cells had been completely reprogrammed to serve as effective cancer killers. In contrast, nonresponders' MANA-oriented CD8 T
cells were sluggish, with significantly more inhibitory proteins produced.

Both responders and nonresponders' MANA-, influenza- or
Epstein-Barr-oriented CD8 T cells had significant differences in their programming as well. The MANA- oriented cells tended to be incompletely activated compared with the other CD8 T cell types. The MANA-oriented
cells were also significantly less responsive to interleukin-7, a molecule
that readies immune cells to fight, compared with influenza-oriented
cells.

Together, Smith says, these findings suggest numerous differences in MANA- oriented cells between checkpoint inhibitor responders and nonresponders
that could eventually serve as drug targets to make nonresponders' CD8
T cells act more like responders' -- both for NSCLC and a broad array
of other cancer types.

"By learning how to reprogram these immune cells, we could someday
facilitate disease-free survival for more people with cancer," says
Smith. She adds that "an important and interesting finding was that nonresponders had cells that recognized the tumor. So there is 'hope'
for developing treatments for patients who don't respond to single
agent immunotherapy. We just need to figure out the right target
to activate these cells to help them do what they were made to do." ========================================================================== Story Source: Materials provided by Johns_Hopkins_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Justina X. Caushi, Jiajia Zhang, Zhicheng Ji, Ajay Vaghasia, Boyang
Zhang, Emily Han-Chung Hsiue, Brian J. Mog, Wenpin Hou, Sune
Justesen, Richard Blosser, Ada Tam, Valsamo Anagnostou, Tricia
R. Cottrell, Haidan Guo, Hok Yee Chan, Dipika Singh, Sampriti Thapa,
Arbor G. Dykema, Poromendro Burman, Begum Choudhury, Luis Aparicio,
Laurene S. Cheung, Mara Lanis, Zineb Belcaid, Margueritta El Asmar,
Peter B. Illei, Rulin Wang, Jennifer Meyers, Kornel Schuebel,
Anuj Gupta, Alyza Skaist, Sarah Wheelan, Jarushka Naidoo, Kristen
A. Marrone, Malcolm Brock, Jinny Ha, Errol L. Bush, Bernard J. Park,
Matthew Bott, David R. Jones, Joshua E.

Reuss, Victor E. Velculescu, Jamie E. Chaft, Kenneth W. Kinzler,
Shibin Zhou, Bert Vogelstein, Janis M. Taube, Matthew D. Hellmann,
Julie R.

Brahmer, Taha Merghoub, Patrick M. Forde, Srinivasan
Yegnasubramanian, Hongkai Ji, Drew M. Pardoll, Kellie
N. Smith. Transcriptional programs of neoantigen-specific TIL in
anti-PD-1-treated lung cancers. Nature, 2021; 596 (7870): 126 DOI:
10.1038/s41586-021-03752-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210921125139.htm

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