Peripheral memory and naïve T cells in non-small cell lung cancer patients with lung metastases..

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Peripheral memory and naïve T cells in non-small cell lung cancer patients with lung metastases undergoing stereotactic body radiotherapy: predictors of early tumor response

Abstract

Background

Further analysis of phase I trial of the KEYNOTE-001 has shown that previous radiotherapy improves the outcomes of patients with advanced non-small cell lung cancer (NSCLC) who received pembrolizumab treatment, possibly explained by the radiation-induced specific anti-cancer immunity with a memory effect. In this study, we aimed to investigate the peripheral memory and naïve T cells as predictors of early response in lung metastases post-stereotactic body radiotherapy (SBRT).


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505218/

[Tamira47]

Hi Debbie,
I found this article very interesting. On my 4th SBRT treatment and have a pembrolizumab infusion the day after the last radiation. Hoping for this effect on my immune system's efficacy.
Miranda.

[D.ap]

Hello Miranda,
Are you on an every 3 week dose of Keytruda?
Are scans due soon ?
If you get a moment could you post in the personel section your story .

Dx’d year
Treatments and metastatic spread .
Thank you .

[D.ap]

Full title of Re: Peripheral memory and naïve T cells in non-small cell lung cancer patients with lung metastases undergoing stereotactic body radiotherapy: predictors of early tumor response

Naïve T cells are essential components of the immune system that enable the body to fight off new, unrecognized infections and diseases. ... Memory T cells are enriched for response to recall antigens. They have a lower activation threshold than naïve T cells, so they are more easily stimulated by antigen in vitro.Sep 5, 2017

A naïve T cell is a T cell that has matured and been released by the thymus but has not yet encountered its corresponding antigen. In other words, naïve T cells are in the stage between maturity and activation. Each naïve T cell has a unique T cell receptor (TCR) that recognizes a specific antigen.

Ask A Scientist: What’s the Difference Between Naïve and Memory T Cells?

September 5, 2017

We’re often asked about naïve T cells and memory T cells; specifically if we have both types in our inventory. We do carry both types of CD4+ T cells from multiple donors, and savvy researchers know when to ask for each.

Naïve T cells are essential components of the immune system that enable the body to fight off new, unrecognized infections and diseases. You can use naïve T cells to develop T regulatory cells, or skew cytokine expression patterns to TH1 or TH2 types.

Memory T cells are enriched for response to recall antigens. They have a lower activation threshold than naïve T cells, so they are more easily stimulated by antigen in vitro. Memory T cells are critical for understanding effective vaccinations, studying antigen-specific immune system responses, and testing checkpoint inhibitors.

For more information on the similarities and differences between naïve and memory T cells, view the information below.

Comparing Naïve and Memory T Cells

Naïve T Cells

Origin:

Bone marrow
Thymus

Phenotype:

Express CD45RA, CD62L, IL-7 receptors
Absence of CD25, CD44, CD69, memory CD45RO
Quiescent, non-dividing

Function:

Respond to antigens the immune system has never encountered
Recognize cognate antigen and initiate an immune response
Enable immune system to respond to new pathogens

Use Cases:

Developing T cells with distinct cytokine expression patterns (TH1/TH2/TH17)
Making T regulatory cells



Memory T Cells

Origin:

Lymph nodes
Peripheral circulation
Tissue

Phenotype:

Central Memory T Cells (TCM): Express CD45RO, CCR7, CD62L, CD44
Effector Memory T Cells (TEM): Express CD45RO, Absence of CCR7, CD62L

Function:

Recognize and respond to bacteria, viruses and cancer cells previously encountered
Respond to antigens the immune system has encountered through infection or vaccination

Use Cases:

Vaccine development
T lymphocyte proliferation assays
Studying antigen-specific responses and checkpoint inhibitors

Author: Anne Lodge, Ph.D.

https://cellero.com/blog/ask-scientist- ... y-t-cells/

Migration, maintenance and recall of memory T cells in peripheral tissues


Abstract

After the resolution of an immune response, antigen-specific memory T cells persist at many sites in the body. The antigen-specific memory T-cell pool includes memory T cells that preferentially reside in peripheral tissues, such as the skin, gut and lungs, where they provide a first line of defence against secondary pathogen infection. Determining how peripheral memory T cells are regulated is essential for our understanding of host−pathogen interactions and for vaccine development. In this Review, we discuss recent insights into the generation, control and recall of peripheral T-cell memory responses.



https://www.nature.com/articles/nri2496

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Migration, maintenance and recall of memory T cells in peripheral tissues ,continued ..

Main

The mucosal surfaces of the respiratory, intestinal and genital tracts, as well as abrasions of the skin, are major portals of entry into the body for many pathogens. Given that the total surface area of all of these peripheral sites can be more than 400 m2, effective surveillance poses a formidable challenge for the immune system. During an infection, the immune system not only makes a rapid pathogen-specific response at these sites to destroy the invading pathogen, but also generates long-lived memory T cells that can persist at peripheral sites for many months. However, our understanding of how these peripheral memory T cells are regulated is still in its infancy.

The development and propagation of an adaptive immune response specific for an invading pathogen is a highly orchestrated process that involves the activation and proliferation of T cells and their subsequent migration to sites of inflammation. The migration of T cells to peripheral sites is regulated by many factors, including adhesion molecules and chemokine receptors that are expressed by T cells, and integrins, selectins and chemokines that are expressed by cells at various peripheral sites. Effector T cells are preferentially attracted to sites of inflammation and they are highly promiscuous in their migratory patterns. For example, effector T cells can enter all inflamed non-lymphoid tissues, regardless of where the T cells initially encountered antigen1. This allows the immune response to remain flexible should the infection spread to other tissues. After pathogen clearance, the recruitment of effector T cells to the site of infection is slowed by both decreasing levels of inflammation and the sequestration of excess chemokines by decoy receptors and apoptotic cells2,3. Antigen-specific T cells that remain in the body after the contraction of the effector T-cell population are then maintained indefinitely as long-lived memory T cells, which can generate a rapid recall response to secondary pathogen challenge4,5,6. However, in contrast to effector T cells, the migration of memory T cells to non-lymphoid tissues is more restricted, raising questions as to how the trafficking of memory T cells to peripheral sites is controlled and what role peripheral memory T cells have in the protection against secondary pathogen challenge.

In this Review, we discuss recent evidence that describes the cellular interactions that are required for the generation of peripheral memory T-cell populations, the mechanisms by which these cells are maintained, the role of these cells in resistance to secondary infections and how these insights can be used to improve existing vaccination strategies.

[Tamira47]

Hello Debbie, Olga...any admin or ASPS worrior
I had about 4 visible lung mets from a November scan. All other areas are clear so far...brain, original met site(thigh) etc..
Did radiation(SBRT) of a 1.9cm nodule. here are March scan results post radiation and back on keytruda/axi

A 1.9cm one that was radiated in December 2021, now 1.1cm on a March 2022 scan
A 0.7cm met now 1.2cm ( growth)
A 0.5cm met from Nov, stable in March
A 0.1cm met from Nov, now stable.

My oncologist wants me to start the anlotinib trial as there is measured progression to make it easier to get on there. I`m thinking about this but I also wonder if it will be better to surgically remove the growing met or radiate it. I do have a cough and have a hard time with breathing when I go up the stairs. I`m able to play tennis though, but have to take breathing breaks. My oncologist believes the radiation may be the cause and is worried about radiating the growing nodule due to said breathing issues. She does encourage the physical activity to open up the lung. These nodules are in my left lung. I`m just unsure the path to take here. What if the anlotinib does not work for me and the nodule grows faster and spreads? Also, if I remove the nodule or radiate it, I don`t qualify for the trial. I was told there is a 30-40% chance shrinkage is greater than 30%. I`ve been on keytruda/axitinib for almost 3 years now. Diagnosed in June of 2017. Any perspective will be helpful as we make this choice.
There are cysts on my liver that have been the same size for years and considered benign.

Thank you,
Miranda.

[D.ap]

Hi Miranda,
Is the tumor that has grown , able to be removed without a lot of lung removed?

What’s your prior history, re: metastasis from 2017 , that Keytruda has resolved ? Your primary has been removed ?
How close was the radiated 1.9cm tumor to the tumor that increased by 5mm? Did you have the lung scans performed at the same radiological place ?
Whewww. Sorry for all the long winded questions!🥴

[Tamira47]

Hi Debbie,
No worries. I don't mind the questions at all.
The primary was under 5cm in the right thigh. Was removed in 2017 prior to identification as malignant. It was twisted, tumor bed resected, and again later due to infection. It's been clean ever since.

The radiated tumor is at the very top( around fissure line of lower left lung) and growing tumor at upper left lobe. I'm not sure how much lung I'll lose if removed.

Been on keytruda , 3 yrs in June. It held rumors stable for a bit, and then some started growing. There don't seem to be new tumors, although the growing one seemed to have always right after surgery.

[D.ap]

Hello again Miranda,

Thanks for the additional info.
Did the oncologist discuss possible pseudo progression? After your radiation treatments, maybe the tumor reacted as your body developed an equilibrium , for a lack of a better term ? A systemic fluid response ? Homeostasis .

How are your liver values etc.?

I would imagine Olga would like to move our conversation to a personal post.

Did you discontinue axitinib at some point and then restart ,because tumors can progress when a tki is stopped ..Tumor flair and or rebound . How long have you been on axitinib?

[D.ap]

Miranda,
My Pseudo progression search brought this up

https://cureasps.org/forum/viewtopic.php?p=14008#

Successful checkpoint inhibitor therapy can induce immune cell infiltration with a subsequent increase in tumor volume [11], i.e. pseudoprogression, which can be followed by a partial or complete response. This observation led to the development of the immune-related response criteria (irRC, 7) which define progression as an increase of tumor burden of at least 25% at 2 different time points with an interval of at least 4 weeks [7]. Both patients had progressive disease in the CT scans shortly before pathologic examinations revealed scarred, tumor-free metastases even when applying immune-related response criteria

[Tamira47]

Hi Debbie,
No worries. I don't mind the questions at all.
The primary was under 5cm in the right thigh. Was removed in 2017 prior to identification as malignant. It was radiated, tumor bed resected, and again later due to infection. It's been clear ever since.

The radiated tumor is at the very top (around fissure line of lower left lung) of the lower left lung and growing tumor at upper left lobe. I'm not sure how much lung I'll lose if the growingone is removed.

Been on keytruda and axitinib 3 yrs in June. It held rumors stable for a bit, and then some started growing. There doesn't seem to be new tumors, although the growing one seemed to have 'appeared' right after surgery. Then again, that's at the spot where the pathology report post surgery had a potential positive margin.
Liver function tests are all normal.

[D.ap]

Hi Miranda ,
Remind us of what surgery was performed?
Where ?
5mm growth maybe could be with a 2mm plus or minus variation depending on the technician doing the scan ?
With surgeries /radiation, there sure could be a degree of growth and as the body accumulates , develops an equilibrium, may reduce?
Your radiation was scheduled before or after surgery ?

I guess my point is Anlotinib is a different Med and could be alot harsher than your current regiment with Keytruda and axitinib.

Maybe wait for your next 3 month scan results?

[D.ap]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505218/

Discussion
Few studies have investigated tumor response predictors after SBRT. One of those, a recent study, revealed that the mean and maximum values of pre-SBRT standard uptake value could predict a complete response in lung metastases from various primary tumors 6 months after SBRT [27]. In addition, a minimum 20% shrinkage in lung lesion during the final SBRT was revealed to correlate positively with a complete response, 6 months after SBRT [27, 28]. Here, we have provided additional information, that peripheral memory CD4+ T, memory CD8+ T, naïve CD4+ T, and CD4+ naïve/memory ratio were independent tumor response predictors to SBRT in NSCLC lung metastases.

CD45RO has been identified as a common marker of all subdivisions of memory T-cells, such as subdivisions of the bone marrow and secondary lymphoid organs, and subdivisions of circulating and tissue-resident nature, but it is not known to mark T memory-stem cells [29]. The elimination of an antigen necessitates the generation of Memory T cells during cell-mediated immune responses, and these generated cells last months and years after the antigens are gone, causing quicker and bigger responses to secondary and ensuing antigen exposures [30]. Upon tumor antigen stimulation, activated memory CD4+ T cells respond very early to impede extensive replication or any significant impairment, either directly attacking the invading organism or providing assistance to B or cytotoxic T cells [31]. Memory CD8+ T cells have the ability to persist for years and kill tumor and virally infected cells [32].

The prognostic value of tumor-infiltrating memory T cells has been assessed by many researchers in lung cancer. Memory T cells that infiltrate tumors in lymph-node metastases reportedly are positive independent factors of prognosis for survival in patients with NSCLC [33]. A positive correlation between tumor-associated memory T cells and survival of SCLC patients has been shown to exist [34]. Interestingly, the correlation between memory T cells that infiltrate renal cell carcinoma and survival was negative, possibly due to impaired infiltrating lymphocytes within the renal cell carcinoma [35]. In our study, we found more memory CD4+ T and CD8+ T cells in responders than non-responders in lung metastases undergoing SBRT. In multivariate logistic regression analysis, memory CD4+ T and CD8+ T were independent predictors of tumor response to SBRT, consistent with the function of memory cells.

Also, we found fewer naïve CD4+ T cells, CD4+ naïve/memory ratio, and CD8+ naïve/memory ratio in responders than non-responders and an unfavorable predictive value of naive CD4+ T and CD4+ naïve/memory ratio for tumor response after SBRT. Recently, Su et al. [36] reported that the chemotaxis of circulating naive CD4+ T cells differentiating into Tregs in situ and causing immunosuppression of tumors trigger the infiltration of breast tumors by Tregs, which may explain our findings on naïve CD4+ T.

Several limitations exist in our study. First, different histological types were enrolled, including adenocarcinoma and squamous cell carcinoma. Second, the sample size of 66 patients was limited and the study contained an unavoidable selection bias. Third, different doses of SBRT were used in our study. Finally, although the tumor response was evaluated 1 month after SBRT, we were unable to evaluate it after 6 months, since most patients went back to their local hospitals 1 month after SBRT. Nevertheless, our study could potentially be a step towards providing additional biomarkers for predicting tumor response after SBRT.

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Conclusions
We revealed that peripheral memory CD4+ T, memory CD8+ T, naïve CD4+ T, and CD4+ naïve/memory ratio were independent predictors for tumor response to SBRT in NSCLC lung metastases. Larger, in-depth studies are necessary to verify our findings.

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Additional file
Additional file 1: Figure S1. Representative flow cytometry plots and gating for (A) memory CD4+ T and naïve CD4+ T cells, (B) memory CD8+ T and naive CD8+ T cells.(608K, docx)
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