For non-small cell lung cancer, T cell repertoire in lungs affects survival

Surveying the landscape of T cell presence and activity across the lungs of patients treated for localized non-small cell lung cancer, researchers have found that what matters most are T cells found in normal tissue.

When the tumor and uninvolved normal tissue elsewhere in the lung share high proportions of T cells, the immune response is less focused on the tumor and more distracted by the pursuit of viruses and other inflammatory targets present in the lung. The result: higher likelihood of cancer relapse and shorter survival.

“The T cell repertoire in the tumor alone did not correlate with disease recurrence, an unexpected  finding, but when we looked at the normal lung, we found surprising impacts,” says Jianjun Zhang, M.D., Ph.D., assistant professor of Thoracic/Head and Neck Medical Oncology and senior author of a new paper in Nature Communications.

Patients treated for localized lung cancer have potentially curative surgery and don’t automatically have radiation or chemotherapy after surgery.

“The only thing that keeps the cancer from coming back is immune cells, particularly T cells,” Zhang says. “So the initial goal was to find whether T cell parameters are associated with the risk of post-surgical recurrence.”

Zhang and colleagues analyzed the tumors and nearby normal lung tissue of 236 patients treated for localized disease and also looked at the lungs of 11 patients with chronic obstructive pulmonary disease and 24 healthy subjects.

They looked at the raw number of T cells (density), how varied the T cells were in their targets (richness) and how many were activated and expanding (clonality).

More activated T cells in normal lung tissue

Tumors had both greater T cell density and richness than the normal lung tissue, but, surprisingly, the normal tissue had higher clonality – more activated T cells.

One possible explanation is the immunosuppressive microenvironment of tumors stifles clonality, says study first author Alexandre Reuben, Ph.D., assistant professor of Thoracic/Head and Neck Medical Oncology.

“Another hypothesis for this is the lung is an open organ, it’s continuously exposed to the environment, resulting in viral infections, bacterial infections, fungal infections, air pollution, smoking,” Reuben notes.  

“So maybe some of the T cells that we're looking at in the tumor and in the normal lung tissue are not related to cancer at all,” Reuben says. An analysis with collaborators from Stanford showed that a high percentage of those T cells target viruses.

The team also found that 57 of the top 100 most active T cell clones in the tumor were also present in the uninvolved lung tissue and 28 of them are among the top 100 most active in uninvolved lung tissues.

T cells distracted by non-tumor targets

“One reason there are so many shared T cells between the normal tissue and the tumor is because many are actually fighting the viruses, they’re not fighting cancer cells at all,” Zhang says.

Massive amounts of T cells combating infections, inflammation or background mutations unrelated to cancer limit the immune system’s capacity to mount a large, tumor-specific army of T cells, Zhang says.

A more tumor-focused T cell repertoire in the lung is associated with improved survival.

Patients with low density of T cells in normal tissue had a median survival of 8.2 years, compared to 4.4 years for those with high density of T cells in normal tissue.

Those with low T cell activation (clonality) in the normal tissue had median survival of 7.2 years, compared to 4.5 years for those with high clonality.

They also found a positive indicator for survival. Patients with higher density of T cells in their blood had median survival of 10.5 years compared to 5.6 years for those with lower density, suggesting increased systemic immunity.

“These findings have major therapeutic implications and could explain why some patients don’t respond to immunotherapy because the wrong populations of T cells are targeted,” says Zhang.

Immune checkpoint blockade drugs that inhibit the PD-1 brake on T cells, for example, help around 20 to 25%of later-stage lung cancer patients. These drugs, which protect T cells from deactivation, could also be firing up T cells that cause pneumonitis, inflammation of the lungs, side effect affecting 3%of patients.

A developing potential treatment, tumor-infiltrating lymphocytes (TILs), consists of gathering T cells that have penetrated a tumor, vastly expanding them in the lab, and then giving them back to patients to better combat the disease. These T cells’ antigen targets are not known, but they are thought to have anti-tumor potential because they were found inside the cancer.

This approach works in some cancer types, such as melanoma. “Unselective expansion of TILs may not be ideal for lung cancers because it may lead to suboptimal anti-tumor activity due to distraction from non-tumor specific T cells and high risks of toxicity from T cells targeting background mutations present in normal tissues,” Zhang says.

It might be necessary to use new, developing techniques to identify the antigens that the T cell receptor (TCR) on the TILs attacks, at least for lung cancers. Those that target only viruses might be culled and only those that target tumor antigens expanded and infused back into patients, Reuben says.

“One of the main goals of Alex’s lab is to figure out the TCRs that are specific to tumors,” Zhang notes.

Reuben’s lab is dedicated to that painstaking work, applying TCR sequencing, single-cell sequencing and functional studies, as well as developing novel approaches to better characterize T cells and their targets.

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